Histology_Ross

Histology_Ross. For years, cardiologists and nephrologists believed that chronic essential hypertension, the most common form of hypertension, was somehow related to an abnor-mality in the RAAS. However, 24-hour urine renin levels in such patients were usually normal. Not until a factor in the venom of a South American snake was shown to be a potent inhibitor of angiotensin-converting enzyme (ACE) in the lung did investigators have both a clue to the cause of chronic essential hypertension and a new series of drugs with which to treat this common disease. The “lesion” in chronic essential hypertension is now be-lieved to be excessive production of angiotensin II in the lung. Development of the so-called ACE inhibitors—captopril, enalapril, and related derivatives of the original snake venom factor—has revolutionized the treatment of chronic essential hypertension. These antihypertensive drugs do not cause the often-dangerous side effects of the diuretics and -blockers that were previously the most


Histology_Ross

Histology_Ross. revolutionized the treatment of chronic essential hypertension. These antihypertensive drugs do not cause the often-dangerous side effects of the diuretics and -blockers that were previously the most commonly used drugs for control of this condition.


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Histology_Ross.  FOLDER 20.4 Clinical Correlation: Renin–Angiotensin– Aldosterone System (RAAS) and Hypertension Angiotensin II is also a potent vasoconstrictor that has a regulatory role in the control of renal and systemic vascu lar resistance.


Histology_Ross

Histology_Ross. The juxtaglomerular apparatus functions not only as an endocrine organ that secretes renin but also as a sensor of blood volume and tubular fluid composition. The cells of the macula densa monitor the Na concentration in the tubular fluid and regulate both the glomerular filtration rate and the release of renin from the juxtaglomerular cells. The decreased Na concentration in the distal convoluted tubule is believed to be a stimulus for unique ion-transporting molecules expressed on the apical membrane of macula densa cells. These molecules include Na/2Cl /K cotransporters, Na/H exchangers, and pHand calcium-regulated K channels. Activation of membrane transport pathways changes the intracellular ion concentration within the macula densa cells and initiates signaling mechanisms by releasing various mediators such as ATP, adenosine, nitric oxide (NO), and prostaglandins (PGE2). These molecules act in a paracrine manner and signal both the underlying juxtaglomerular cells of the


Histology_Ross

Histology_Ross. releasing various mediators such as ATP, adenosine, nitric oxide (NO), and prostaglandins (PGE2). These molecules act in a paracrine manner and signal both the underlying juxtaglomerular cells of the afferent arteriole to secrete renin and the vascular smooth muscle cells to contract. An increase in blood volume sufficient to cause stretching of the juxtaglomerular cells in the afferent arteriole may be the stimulus that closes the feedback loop and stops secretion of renin.


Histology_Ross

Histology_Ross. As the glomerular ultrafltrate passes through the uriniferous and collecting tubules of the kidney, it undergoes changes that involve both active and passive absorption, as well as secretion. Certain substances within the ultrafiltrate are reabsorbed, some partially (e.g., water, sodium, and bicarbonate) and some completely (e.g., glucose). Other substances (e.g., creatinine and organic acids and bases) are added to the ultrafiltrate (i.e., the primary urine) by secretory activity of the tubule cells. Thus, the volume of the ultrafiltrate is reduced substantially, and the urine is made hyperosmotic. The long loop of Henle and the collecting tubules that pass parallel to similarly arranged blood vessels, the vasa recta, serve as the basis for the countercurrent multiplier mechanism that is instrumental in concentrating the urine, thereby making it hyperosmotic. The proximal convoluted tubule is the initial and major site of reabsorption.


Histology_Ross

Histology_Ross. The proximal convoluted tubule receives the ultrafiltrate from the urinary space of Bowman’s capsule. The cuboidal cells of the proximal convoluted tubule have the elaborate surface specializations associated with cells engaged in absorption and fluid transport. They exhibit the following features:  A brush border, composed of relatively long, closely packed, and straight microvilli (Fig. 20.17)  A junctional complex, consisting of a narrow, tight junction that seals off the intercellular space from the lumen of the tubule and a zonula adherens that maintains the adhesion between neighboring cells  Plicae or folds located on the lateral surfaces of the cells, which are large flattened processes, alternating with similar processes of adjacent cells (see Fig. 20.16)  Extensive interdigitation of basal processes of adjacent cells (Figs. 20.18 and 20.19)  Basal striations, consisting of elongate mitochondria concentrated in the basal processes and oriented vertically to the basal


Histology_Ross

Histology_Ross. of basal processes of adjacent cells (Figs. 20.18 and 20.19)  Basal striations, consisting of elongate mitochondria concentrated in the basal processes and oriented vertically to the basal surface (see Fig. 20.18)


Histology_Ross

Histology_Ross. In well-fixed histologic preparations, the basal striations and the apical brush border help to distinguish the cells of the proximal convoluted tubule from those of the other tubules. At the very base of the proximal convoluted tubule cell, in the interdigitating processes, bundles of 6-nm microfilaments FIGURE 20.17 • Drawing of proximal convoluted tubule cells.


Histology_Ross

Histology_Ross. The drawing, at the electron microscopic level, shows the sectioned face on the right and a three-dimensional view of the basolateral surface of a cell with a partial cut face on the left. Here the interdigitating parts of the adjoining cell have been removed to show the basolateral interdigitations. Some of the interdigitating processes extend the full height of the cell. The processes are long in the basal region and create an elaborate extracellular compartment adjacent to the basal lamina. Apically, the microvilli (M) constitute the brush border. In some locations, the microvilli have been omitted, thereby revealing the convoluted character of the apical cell boundary (CB). (Based on Bulger RE. The shape of rat kidney tubular cells. Am J Anat 1965;116:253.) are present (see arrows, Figs. 20.18 and 20.19). These actin filaments may play a role in regulating the movement of fluid from the basolateral extracellular space across the tubule basal lamina toward the adjacent peritubular


Histology_Ross

Histology_Ross. 20.18 and 20.19). These actin filaments may play a role in regulating the movement of fluid from the basolateral extracellular space across the tubule basal lamina toward the adjacent peritubular capillary.


Histology_Ross

Histology_Ross. Of the 180 L/day of ultrafiltrate entering the nephrons, approximately 120 L/day, or 65% of the ultrafiltrate, is reabsorbed by the proximal convoluted tubule. Two major proteins are responsible for fluid reabsorption in the proximal convoluted tubules:


Histology_Ross

Histology_Ross. FIGURE 20.18 • Electron micrograph of a proximal tubule cell. The apical surface of the cell shows the closely packed microvilli (Mv) that collectively are recognized as the brush border in the light microscope. Many vesicles (V) are evident in the apical cytoplasm. Also present in the apical region of the cell are lysosomes (L). The nucleus has not been included in the plane of section. Extensive numbers of longitudinally oriented mitochondria (M) are present in the cell within the interdigitating processes. The mitochondria are responsible for the appearance of the basal striations seen in the light microscope, particularly if the extracellular space is enlarged. The electron micrograph also reveals a basal lamina and a small amount of connective tissue and the fenestrated endothelium (En) of an adjacent peritubular capillary. 15,000. Upper inset. This higher magnification of the microvilli shows the small endocytotic vesicles that have pinched off from the plasma membrane at the


Histology_Ross

Histology_Ross. (En) of an adjacent peritubular capillary. 15,000. Upper inset. This higher magnification of the microvilli shows the small endocytotic vesicles that have pinched off from the plasma membrane at the base of the microvilli. 32,000. Lower inset. A higher magnification of the basal portion of the interdigitating processes (IP) below the reach of the mitochondria. The extreme basal aspect of these processes reveals a dense material (arrows) that represents bundles of actin filaments (see Fig. 20.16). 30,000.


Histology_Ross

Histology_Ross. FIGURE 20.19 • Electron micrograph of a proximal convoluted tubule cell. This section is almost tangential and slightly oblique to the base of a proximal convoluted tubule cell and the subjacent basal lamina and capillary. In the left part of the micrograph is the capillary endothelium (En). Characteristically, the endothelium possesses numerous fenestrations (EnF), and in this plane of section, the fenestrations are seen en face, displaying circular profiles. The plane of section also makes the basal lamina (BL) appear as a broad band of homogenous material. To the right of the basal lamina are the interdigitating basal processes of the proximal tubule cells. The long, straight processes contain longitudinally oriented actin filaments (arrows). In this plane of section, the basal extracellular space appears as a maze between the cellular processes. 32,000.


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Histology_Ross.  Na/K-ATPase pumps, transmembrane proteins that are localized in the lateral folds of the plasma membrane. They are responsible for the reabsorption of Na, which is the major driving force for reabsorption of water in the proximal convoluted tubule. As in the intestinal and gallbladder epithelia, this process is driven by active transport of Na into the lateral intercellular space. Active transport of Na is followed by passive diffusion of Cl to maintain electrochemical neutrality. The accumulation of NaCl in the lateral intercellular spaces creates an osmotic gradient that draws water from the lumen into the intercellular compartment. This compartment distends as the amount of fluid in it increases; the lateral folds separate to allow this distension.


Histology_Ross

Histology_Ross.  AQP-1, a small (30 kilodaltons) transmembrane protein that functions as a molecular water channel in the cell membrane of proximal convoluted tubules. Movement of water through these membrane channels does not require the high energy of Na/K-ATPase pumps. Immunocytochemical methods can be used to demonstrate the presence of these proteins.  The hydrostatic pressure that builds up in the distended intercellular compartment, presumably aided by contractile activity of the actin filaments in the base of the tubule cells, drives an essentially isosmotic fluid across the tubule basement membrane into the renal connective tissue. Here, the fluid is reabsorbed into the vessels of the peritubular capillary network. The proximal convoluted tubule also reabsorbs amino acids, sugars, and polypeptides.


Histology_Ross

Histology_Ross. The proximal convoluted tubule also reabsorbs amino acids, sugars, and polypeptides. As in the intestine, the microvilli of proximal convoluted tubule cells are covered with a well-developed glycocalyx that contains several ATPases, peptidases, and high concentrations of disaccharidases. In addition to amino acids and monosaccharides, the ultrafiltrate also contains small peptides and disaccharides. The latter adsorb on the glycocalyx for further digestion before internalization of the resulting amino acids and monosaccharides (including glucose). Also, as in the gut, amino acid and glucose resorption in the proximal convoluted tubule depends on active Na transport. Proteins and large peptides are endocytosed in the proximal convoluted tubule.


Histology_Ross

Histology_Ross. Proteins and large peptides are endocytosed in the proximal convoluted tubule. Deep tubular invaginations are present between the microvilli of the proximal convoluted tubule cells. Proteins in the ultra-filtrate, on reaching the tubule lumen, bind to the glycocalyx that covers the plasma membrane of the invaginations. Then endocytotic vesicles containing the bound protein bud from the invaginations and fuse in the apical cytoplasm to form large protein-containing early endosomes (see Fig. 20.18). These early endosomes are destined to become lysosomes, and the endocytosed proteins are degraded by acid hydro-lases. The amino acids produced in the lysosomal degradation are recycled into the circulation via the intercellular compartment and the interstitial connective tissue.


Histology_Ross

Histology_Ross. Also, the pH of the ultrafiltrate is modified in the proximal convoluted tubule by the reabsorption of bicarbonate and by the specific secretion into the lumen of exogenous organic acids and organic bases derived from the peritubular capillary circulation. The cells of the proximal straight tubule (i.e., the thick descending limb of the loop of Henle) are not as specialized for absorption as are those of the proximal convoluted tubule.  FOLDER 20.5 Functional Considerations: Structure and Function of Aquaporin Water Channels


Histology_Ross

Histology_Ross. Aquaporins (AQPs) are a recently recognized family of nodes, endothelial cells lining lymphatic sinuses, and on small, hydrophobic, transmembrane proteins that mediate the vascular endothelium of high endothelial venules as water transport in the kidney and other organs (i.e., liver, well as in the endothelial cells of intestinal lacteals. gallbladder). To date, 13 proteins have been characterized  AQP-2, present in the terminal portion of the distal con-and cloned. The molecular size of AQPs ranges from 26 to voluted tubules and in the epithelium of collecting34 kilodaltons. Each protein consists of six transmembrane tubules and ducts. AQP-2 is under the regulation of an-domains arranged to form a distinct pore. The sites where tidiuretic hormone (ADH) and is thus known as an ADH-AQPs are expressed implicate their role in water transport, regulated water channel. Mutation of the AQP-2 gene such as renal tubules (water reabsorption), brain and spinal has been linked to congenital


Histology_Ross

Histology_Ross. are expressed implicate their role in water transport, regulated water channel. Mutation of the AQP-2 gene such as renal tubules (water reabsorption), brain and spinal has been linked to congenital nephrogenic diabetes cord (cerebrospinal fluid reabsorption), pancreatic acinar insipidus.


Histology_Ross

Histology_Ross. cells (secretion of pancreatic fluids), lacrimal apparatus (secretion and resorption of tears), and eye (aqueous  AQP-3 and AQP-4 have also been detected in the bahumor secretion and reabsorption). Most AQPs are selec-solateral cell surface of the light cells of kidney collecttive for the passage of water (AQP-1, AQP-2, AQP-4, ing ducts as well in the gastrointestinal epithelium AQP-5, AQP-6, and AQP-8), whereas others, such as (AQP-3), pancreatic acinar cells (AQP-12), and the AQP-3, AQP-7, and AQP-9, called aquaglyceroporins, also brain and spinal cord (AQP-4). transport glycerol and other larger molecules in addition to


Histology_Ross

Histology_Ross. AQP-3, AQP-7, and AQP-9, called aquaglyceroporins, also brain and spinal cord (AQP-4). transport glycerol and other larger molecules in addition to Current research into the function and structure of the water. Prominent members of the AQP family include AQP proteins may lead to the development of water chan  AQP-1, expressed in kidney (proximal convoluted nel blockers that could be used to treat hypertension, con-tubules) and other cell types such as hepatocytes and gestive heart failure, and brain swelling and to regulate red blood cells. AQP-1 is also expressed in the lymph intracranial or intraocular pressure. They are shorter, with a less well-developed brush border and with fewer and less complex lateral and basolateral processes. The mitochondria are smaller than those of the cells of the convoluted segment and are randomly distributed in the cytoplasm. There are fewer apical invaginations and endocytotic vesicles, as well as fewer lysosomes. Thin Segment of Loop of Henle


Histology_Ross

Histology_Ross. Thin Segment of Loop of Henle As noted above, the length of the thin segment varies with the location of the nephron in the cortex. Juxtamedullary nephrons have the longest limbs; cortical nephrons have the shortest. Furthermore, various cell types are present in the thin segment. In the light microscope, it is possible to detect at least two kinds of thin segment tubules, one with a more squamous epithelium than the other. Electron microscopic examination of the thin segments of various nephrons reveals further differences, namely, the existence of four types of epithelial cells (Fig. 20.20):  Type I epithelium is found in the thin descending and ascending limbs of the loop of Henle of short-looped nephrons. It consists of a thin, simple epithelium. The cells have almost no interdigitations with neighboring cells and few organelles.


Histology_Ross

Histology_Ross.  Type II epithelium, found in the thin descending limb of long-looped nephrons in the cortical labyrinth, consists of taller epithelium. These cells possess abundant organelles and have many small, blunt microvilli. The extent of lateral interdigitation with neighboring cells varies by species.  Type III epithelium, found in the thin descending limb in the inner medulla, consists of a thinner epithelium. The cells have a simpler structure and fewer microvilli than type II epithelial cells. Lateral interdigitations are absent.  Type IV epithelium, found at the bend of long-looped nephrons and through the entire thin ascending limb, consists of a low, flattened epithelium without microvilli. The cells possess few organelles.


Histology_Ross

Histology_Ross. The specific functional roles of the four cell types in the thin segment are not yet clear, although this segment is part of the countercurrent exchange system that functions in concentrating urine. Morphologic differences, such as microvilli, mitochondria, and degree of cellular interdigitation, probably reflect specific active or passive roles in this process. The thin descending and ascending limbs of the loop of Henle differ in structural and functional properties.


Histology_Ross

Histology_Ross. Studies of ultrafiltrate that enters the thin descending limb and leaves the thin ascending limb of the loop of Henle reveal dramatic changes in ultrafiltrate osmolality. The ultrafiltrate that enters the thin descending limb is isosmotic, whereas the ultrafiltrate leaving the thin ascending limb is hyposmotic to plasma. This change is achieved by reabsorbing more salts than water. The two limbs of the loop of Henle have different permeabilities and thus different functions:  The thin descending limb of the loop of Henle is highly permeable to water and much less permeable to solutes like NaCl and urea. Because the interstitial fluid in the medulla is hyper-osmotic, water diffuses out of this nephron segment. In addition, a small amount of NaCl and urea enters the nephron at this site. The cells of this limb do not actively transport ions; thus the increased tubular fluid osmolality that occurs in this nephron segment is caused in large part by the passive movement of water into


Histology_Ross

Histology_Ross. The cells of this limb do not actively transport ions; thus the increased tubular fluid osmolality that occurs in this nephron segment is caused in large part by the passive movement of water into the peritubular connective tissue.


Histology_Ross

Histology_Ross. FIGURE 20.20 • Schematic diagram of loop of Henle thin-limb epithelial cells. Roman numerals (I–IV) identify the various segments of the epithelium and the region where they are found in the thin limb of the short and long loops of Henle. The diagrams of the epithelium do not include nuclear regions of the epithelial cells. (Modified from Madsen KM, Tisher CC. Physiologic anatomy of the kidney. In: Fisher JW (Ed). Kidney Hormones, London, UK: Academic Press 1986;3:45–100.)  The thin ascending limb of the loop of Henle does not actively transport ions, but it is highly permeable to NaCl and thus allows passive diffusion of NaCl into the interstitium. Cl diffuses into the interstitium following its concentration gradient through Cl conducting channels. Although the energy from ATP is required to open these channels, the movement of Cl is not an example of active transport and does not require Cl -stimulated ATPase activity. Counter ions, in this case Na (the majority) and K, follow


Histology_Ross

Histology_Ross. to open these channels, the movement of Cl is not an example of active transport and does not require Cl -stimulated ATPase activity. Counter ions, in this case Na (the majority) and K, follow passively to maintain electrochemical neutrality. The hyperosmolarity of the interstitium is directly related to the transport activity of the cells in this limb of the loop of Henle.


Histology_Ross

Histology_Ross. Further, the thin ascending limb is largely impermeable to water, so that at this site, as the salt concentration increases in the interstitium, the interstitium becomes hyperosmotic and the fluid in the lumen of the nephron becomes hyposmotic. In addition, epithelial cells lining the thick ascending limb produce an 85-kilodalton protein called uromodulin (Tamm-Horsfall protein) that influences NaCl reabsorption and urinary concentration ability. Uromodulin also modulates cell adhesion and signal transduction by interacting with various cytokines, as well as it inhibits the aggregation of calcium oxalate crystals (preventing kidney stones formation) and provides a defense against urinary tract infection. In individuals with inﬂammatory kidney diseases, a precipitated uromodulin is detected in urine in the form of urinary casts (see Folder 20.3). The distal straight tubule is a part of the ascending limb of the loop of Henle.


Histology_Ross

Histology_Ross. The distal straight tubule (thick ascending limb), as previously noted, is a part of the ascending limb of the loop of Henleand includes both medullary and cortical portions, with the latter located in the medullary rays. The distal straight tubule, like the ascending thin limb, transports ions from the tubular lumen to the interstitium. The apical cell membrane in this segment has electroneutral transporters (synporters) that allow Cl , Na, and K to enter the cell from the lumen. Na is actively transported across the extensive basolateral plications by the Na/K-ATPase pumps; Cl and K diffuse out from the intracellular space by the Cl and K channels. Some K ions leak back into the tubular fluid through K channels, causing the tubular lumen to be positively charged with respect to the interstitium. This positive gradient provides the driving force for the reabsorption of many other ions such as Ca2 and Mg2. Note that this significant movement of ions occurs without the movement of


Histology_Ross

Histology_Ross. interstitium. This positive gradient provides the driving force for the reabsorption of many other ions such as Ca2 and Mg2. Note that this significant movement of ions occurs without the movement of water through the wall of the distal straight tubule, resulting in separation of water from its solutes.


Histology_Ross

Histology_Ross. In routine histologic preparations, the large cuboidal cells of the distal straight tubule stain lightly with eosin, and the lateral margins of the cells are indistinct (Plate 77, page 734). The nucleus is located in the apical portion of the cell and sometimes, especially in the straight segment, causes the cell to bulge into the lumen. As noted above, these cells have extensive basolateral plications, and there are numerous mitochondria associated with these basal folds (Fig. 20.21). They also have considerably fewer and less well-developed microvilli than proximal straight tubule cells (compare Figs. 20.18 and 20.19). The distal convoluted tubule exchanges Na for K under aldosterone regulation. The distal convoluted tubule, located in the cortical labyrinth, is only about one third as long (5 mm) as the proximal convoluted tubule. This short tubule is responsible for  reabsorption of Naand secretion of K into the ultrafiltrate to conserve Na .


Histology_Ross

Histology_Ross. FIGURE 20.21 • Electron micrograph of a distal convoluted tubule cell. The apical surface of the cell displays some microvilli (Mv), but they are not sufficiently long or numerous to give the appearance of a brush border (compare with Fig. 20.15). The nucleus and Golgi apparatus (G) are in the upper portion of the cell. Mitochondria (M) are chiefly in the basal region of the cell within the interdigitating processes (IP). As in the proximal tubule cell, the mitochondria account for the appearance of basal striations in the light microscope. A basal lamina (BL) is seen adjacent to the basal surface of the cell. 12,000.  reabsorption of bicarbonate ions, with concomitant secretion of hydrogen ions, leading to further acidification of the urine.  secretion of ammonium in response to the kidneys’ need to excrete acid and generate bicarbonate.


Histology_Ross

Histology_Ross. Aldosterone, secreted by the adrenal gland and released under stimulation by angiotensin II, increases the reabsorption of Na and secretion of K . These effects increase blood volume and blood pressure in response to increased blood Na concentration.


Histology_Ross

Histology_Ross. The collecting tubules as well as the cortical collecting ducts and medullary collecting ducts are composed of simple epithelium. The collecting tubules and cortical col lecting ducts have flattened cells, somewhat squamous to cuboidal in shape. The medullary collecting ducts have cuboidal cells, with a transition to columnar cells as the ducts increase in size. The collecting tubules and ducts are readily distinguished from proximal and distal tubules by virtue of the cell boundaries that can be seen in the light microscope (Plate 77, page 734). Two distinct types of cells are present in the collecting tubules and collecting ducts:  Light cells, also called collecting duct cells or CD cells, are the principal cells of the system. They are pale-staining cells with true basal infoldings rather than processes that interdigitate with those of adjacent cells. They possess a single primary cilium and relatively few short microvilli (Fig. 20.22). They contain small, spherical mitochondria.


Histology_Ross

Histology_Ross. than processes that interdigitate with those of adjacent cells. They possess a single primary cilium and relatively few short microvilli (Fig. 20.22). They contain small, spherical mitochondria. These cells possess an abundance of antidiuretic hormone (ADH)–regulated water channels, aquaporin-2 (AQP-2), which are responsible for water permeability of the collecting ducts. In addition, aquaporins AQP-3 and AQP-4 are present within the basolateral membrane of these cells.


Histology_Ross

Histology_Ross.  Dark cells, also called intercalated (IC) cells, occur in considerably smaller numbers. They have many mitochondria, and their cytoplasm appears denser. Microplicae, cytoplasmic folds, are present on their apical surface, as well as microvilli. The microplicae are readily observed with the SEM but may be mistaken for microvilli with the TEM (see Fig. 20.22). They do not show basal infoldings but have basally located interdigitations with neighboring cells. Numerous vesicles are present in the apical cytoplasm. The intercalated cells are involved in the secretion of H (-intercalated cells) or bicarbonate (-intercalated cells), depending on the whether the kidneys need to


Histology_Ross

Histology_Ross. FIGURE 20.22 • Scanning electron micrograph of a collecting tubule. This micrograph shows dark cells (asterisks), with numerous short lamellipodia or microridges on their surface, and light cells, each with a primary cilium on its free surface along with small microvilli. The terms light and dark refer to the staining character of sectioned cells and not to the density differences reflecting charge characteristics of the coated surface of the specimen. (Courtesy of Dr. C. Craig Tisher.) excrete acid or alkali. The -intercalated cell actively secretes H into the collecting duct lumen via ATP-depen dent pumps and releases HCO3 via Cl /HCO3 exchangers located in their basolateral cell membrane. The -intercalated cells have opposite polarity and secrete bicarbonate ions into the lumen of the collecting duct. Because of the nature of the diet and thus the need to excrete acid, the epithelium of collecting ducts contains more than -intercalated cells.


Histology_Ross

Histology_Ross. The cells of the collecting ducts gradually become taller as the ducts pass from the outer to the inner medulla and become columnar in the region of the renal papilla. The number of dark cells gradually decreases until there are none in the ducts as they approach the papilla. The connective tissue of the kidney parenchyma, called interstitial tissue, surrounds the nephrons, ducts, and blood and lymphatic vessels. This tissue increases considerably in amount from the cortex (where it constitutes approximately 7% of the volume) to the inner region of the medulla and papilla (where it may constitute more than 20% of the volume).


Histology_Ross

Histology_Ross. In the cortex, two types of interstitial cells are recognized: cells that resemble fbroblasts, found between the basement membrane of the tubules and the adjacent peritubular capillaries, and occasional macrophages. In their intimate relationship with the base of the tubular epithelial cells, the fibroblasts resemble the subepithelial fibroblasts of the intestine. These cells synthesize and secrete the collagen and glycosaminoglycans of the extracellular matrix of the interstitium. In the medulla, the principal interstitial cells resemble myofbroblasts. They are oriented to the long axes of the tubular structures and may have a role in compressing these structures. The cells contain prominent bundles of actin filaments, abundant rough endoplasmic reticulum (rER), a well-developed Golgi complex, and lysosomes. Prominent lipid droplets in the cytoplasm appear to increase and decrease in relation to the diuretic state.


Histology_Ross

Histology_Ross. Most fibroblasts originate within the interstitial tissue through a mechanism called epithelial–mesenchymal transition. The conversion of tubular epithelial cells into a mesenchymal phenotype is initiated by an alteration in the balance of local cytokine concentrations. During persistent injury and chronic inflammation of the kidney parenchyma, fibroblasts increase their numbers and, by secreting excess extracellular matrix, destroy normal interstitial architecture of the kidney. Research studies suggest that in renal fbrosis, more than one third of all disease-related fibroblasts originate from tubular epithelial cells at the site of injury. Proliferation of fibroblasts in response to local mitogens usually leads to irreversible renal failure characterized by tubulointerstitial nephritis. Recent therapeutic interventions in renal fibrosis are directed toward inhibiting fibroblast formation by shifting local cytokine balance in favor of reversal mesenchymal– epithelial transition.


Histology_Ross

Histology_Ross. The countercurrent multiplier system creates hyperosmotic urine. The term countercurrent indicates a flow of fluid in adjacent structures in opposite directions. The ability to excrete hyper-osmotic urine depends on the countercurrent multiplier system that involves three structures:  Loop of Henle, which acts as a countercurrent multiplier. The ultrafiltrate moves within the descending limb of the thin segment of the loop toward the renal papilla and moves back toward the corticomedullary junction within the ascending limb of the thin segment. The osmotic gradients of the medulla are established along the axis of the loop of Henle.  Vasa recta, form loops parallel to the loop of Henle. They act as countercurrent exchangers of water and solutes between the descending part (arteriolae rectae) and ascending part (venulae rectae) of the vasa recta. The vasa recta help to maintain the osmotic gradient of the medulla.


Histology_Ross

Histology_Ross.  Collecting duct in the medulla acts as an osmotic equilibrating device. Modified ultrafiltrate in the collecting ducts can be further equilibrated with the hyperosmotic medullary interstitium. The level of equilibration depends on activation of ADH-dependent water channels (AQP-2). A standing gradient of ion concentration produces hyper-osmotic urine by a countercurrent multiplier effect. The loop of Henle creates and maintains a gradient of ion concentration in the medullary interstitium that increases from the corticomedullary junction to the renal papilla. As noted above, the thin descending limb of the loop of Henle is freely permeable to water, whereas the ascending limb of the loop of Henle is impermeable to water. Further, the thin ascending limb cells add Na and Cl to the interstitium.


Histology_Ross

Histology_Ross. Because water cannot leave the thin ascending limb, the interstitium becomes hyperosmotic relative to the luminal contents. Although some of the Cl and Na of the interstitium diffuses back into the nephron at the thin descending limb, the ions are transported out again in the thin ascending limb and distal straight tubule (thick ascending limb). This produces the countercurrent multiplier effect. Thus, the concentration of NaCl in the interstitium gradually increases down the length of the loop of Henle and, consequently, through the thickness of the medulla from the corticomedullary junction to the papilla. Vasa recta containing descending arterioles and ascending venules act as countercurrent exchangers. For an understanding of the countercurrent exchange mechanism, it is necessary to resume the description of the renal circulation at the point at which the efferent arteriole leaves the renal corpuscle.


Histology_Ross

Histology_Ross. The efferent arterioles of the renal corpuscles of most of the cortex branch to form the capillary network that surrounds the tubular portions of the nephron in the cortex, the peritubular capillary network. The efferent arterioles of the juxtamedullary renal corpuscles form several unbranched arterioles that descend into the medullary pyramid. These arteriolae rectae make a hairpin turn deep in the medullary regulated by antidiuretic hormone (ADH, vasopressin), a hormone produced in the hypothalamus and released from the posterior lobe of the pituitary gland. ADH increases the permeability of the collecting duct to water, thereby producing more-concentrated urine. At the molecu-lar level, ADH acts on ADH-regulated water channels, aqua-porin 2 (AQP-2), located in the epithelium of the terminal portion of the distal convoluted tubule and in the epithelium of the collecting tubules and ducts. However, the action of ADH is more significant in the collecting tubules and collect-ing ducts.


Histology_Ross

Histology_Ross. portion of the distal convoluted tubule and in the epithelium of the collecting tubules and ducts. However, the action of ADH is more significant in the collecting tubules and collect-ing ducts. ADH binds to receptors on the cells of these tubules and triggers the following actions:  Translocation of the AQP-2–containing intracyto-plasmic vesicles into the apical cell surface—a short-term effect. This results in an increased number of available AQP-2 channels at the cell surface, thus increas-ing water permeability of the epithelium.  Synthesis of AQPs-2 and their insertion into the apical cell membrane—a long-term effect volume stimulates release of ADH, as does nicotine. In the absence of ADH, copious, dilute urine is produced. This condition is called central diabetes insipidus (CDI). Recent studies indicate that mutation of two genes encoding AQP-2 and ADH receptors is responsible for a form of CDI called nephrogenic diabetes insipidus. In this disease, the kidney does not


Histology_Ross

Histology_Ross. (CDI). Recent studies indicate that mutation of two genes encoding AQP-2 and ADH receptors is responsible for a form of CDI called nephrogenic diabetes insipidus. In this disease, the kidney does not respond to ADH because of defective AQP-2 and ADH receptor proteins synthesized by the col-lecting tubule and duct epithelial cells. Excess water con-sumption can also inhibit ADH release, thereby promoting the production of a large volume of hyposmotic urine. Increased secretion of ADH can produce an extremely hyperosmotic urine, thereby conserving water in the body. Inadequate consumption of water or loss of water because of sweating, vomiting, or diarrhea stimulates release of ADH. This leads to an increase in the permeability of the epithelium of the distal and collecting tubules and pro-motes the production of a small volume of hyperosmotic urine.


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Histology_Ross.  FOLDER 20.6 Functional Considerations: Hormonal Regulation of Collecting Duct Function Water permeability of the epithelium of the collecting ducts is An increase in plasma osmolality or a decrease in blood pyramid and ascend as the venulae rectae. Together, the descending arterioles and the ascending venules are called the vasa recta. The arteriolae rectae form capillary plexuses lined by fenestrated endothelium that supply the tubular structures at the various levels of the medullary pyramid. Interaction between collecting ducts, loops of Henle, and vasa recta is required for concentrating urine by the countercurrent exchange mechanism.


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Histology_Ross. Interaction between collecting ducts, loops of Henle, and vasa recta is required for concentrating urine by the countercurrent exchange mechanism. Because the thick ascending limb of the loop of Henle has a high level of transport activity and because it is impermeable to water, the modified ultrafiltrate that ultimately reaches the distal convoluted tubule is hyposmotic. When ADH is present, the distal convoluted tubules, the collecting tubules, and the collecting ducts are highly permeable to water. Therefore, within the cortex, in which the interstitium is isosmotic with blood, the modified ultrafiltrate within the distal convoluted tubule equilibrates and becomes isosmotic, partly by loss of water to the interstitium and partly by addition of ions other than Na and Cl to the ultrafiltrate. In the medulla, increasing amounts of water leave the ultrafiltrate as the collecting ducts pass through the increasingly hyperosmotic interstitium on their course to the papillae.


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Histology_Ross. As noted previously, the vasa rectae also form loops in the medulla that parallel the loop of Henle. This arrangement ensures that the vessels provide circulation to the medulla without disturbing the osmotic gradient established by transport of Cl in the epithelium of the ascending limb of the loop of Henle. The vasa recta form a countercurrent exchange system in the following manner: Both the arterial and venous sides of the loop are thin-walled vessels that form plexuses of fenestrated capillaries at all levels in the medulla. As the arterial vessels descend through the medulla, the blood loses water to the interstitium and gains salt from the interstitium so that at the tip of the loop, deep in the medulla, the blood is essentially in equilibrium with the hyperosmotic interstitial fluid.


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Histology_Ross. As the venous vessels ascend toward the corticomedullary junction, the process is reversed (i.e., the hyperosmotic blood loses salt to the interstitium and gains water from the interstitium). This passive countercurrent exchange of water and salt between the blood and the interstitium occurs without expenditure of energy by the endothelial cells. The energy that drives this system is the same energy that drives the multiplier system, namely, the movement of Na and Cl out of the cells of the water-impermeable ascending limb of the loop of Henle. The counter-current exchange system and other movements of molecules in different parts of the nephron are shown in Figure 20.23. Some aspects of the blood supply of the kidney have been described in relation to specific functions (i.e., glomerular filtration, control of blood pressure, and countercurrent exchange). It remains, however, to provide an overall description of the blood supply of the kidney.


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Histology_Ross. Each kidney receives a large branch from the abdominal aorta, called the renal artery. The renal artery branches within the renal sinus and sends interlobar arteries into the substance of the kidney (Fig. 20.24). These arteries travel between the pyramids as far as the cortex and then turn to follow an arched course along the base of the pyramid between the medulla and the cortex. Thus, these interlobar arteries are designated arcuate arteries.


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Histology_Ross. Na+ H2O H2O H2O H2O H2O H2O H2O H2O H2O Cl-Cl-K+ K+ K+ H+ H+ H+glomerulus glucose amino acids polypeptides distal convoluted tubule collecting tubule proximal convoluted tubule loop of Henleurea thin descending limb collecting duct MEDULLA CORTEX urea distal straight tubule H2O Na+ organic acids Ca2+ Mg2+ Na+ Na+ Na+ Cl-thin ascending limb proximal straight tubule Active transport Active exchange Active cotransport Passive diffusion ADH-dependent H2O movement Aquaporin-dependent H2O movement (AQP)2 2 2 3 3 H+ bicarbonate anion bicarbonate anion Na+ Na+ K+ 1 1 K+K+ Cl- FIGURE 20.23 • Diagram showing movement of substances into and out of the nephron and collecting system. The symbols indicate the mode of transport as noted in the key.


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Histology_Ross. FIGURE 20.23 • Diagram showing movement of substances into and out of the nephron and collecting system. The symbols indicate the mode of transport as noted in the key. Interlobular arteries branch from the arcuate arteries and ascend through the cortex toward the capsule. Although the boundaries between lobules are not distinct, the interlobular arteries, when included in a section cut perpendicular to the vessel, are located midway between adjacent medullary rays, traveling in the cortical labyrinth. As they traverse the cortex toward the capsule, the interlobular arteries give off branches, the afferent arterioles, one to each glomerulus. A single afferent arteriole may spring directly from the interlobular artery, or a common stem from the interlobular artery may branch to form several afferent arterioles. Some interlobular arteries terminate near the periphery of the cortex, whereas others enter the kidney capsule to provide its arterial supply.


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Histology_Ross. Afferent arterioles give rise to the capillaries that form the glomerulus. The glomerular capillaries reunite to form an efferent arteriole that, in turn, gives rise to a second network of capillaries, the peritubular capillaries. The arrangement of these capillaries differs according to whether they originate from cortical or juxtamedullary glomeruli.  Efferent arterioles from cortical glomeruli lead into a peritubular capillary network that surrounds the local uriniferous tubules (G1 and G2, Fig. 20.24).  Efferent arterioles from juxtamedullary glomeruli descend into the medulla alongside the loop of Henle; they break up into smaller vessels that continue toward the apex of the pyramid but make hairpin turns at various levels to


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Histology_Ross. FIGURE 20.24 • Schematic diagram of the renal blood supply. The renal artery gives rise to interlobar arteries that branch into arcuate arteries at the border between the medulla and cortex. Interlobular arteries (IL) branch from the arcuate arteries and travel toward the renal capsule, giving off afferent arterioles to the glomeruli (G). Glomeruli in the outer part of the cortex (G1, G2) send efferent arterioles to the peritubular capillaries (PC) that surround the tubules in the cortex; glomeruli near the medulla (G3), the juxtamedullary glomeruli, send efferent arterioles almost entirely into the medullary plexus (MP) of capillaries via the arteriolae rectae spuriae (ARS). Blood returns from the capillaries via veins that enter the arcuate veins. Stellate veins (SV) near the capsule drain both the capsular (CC) and the peritubular capillaries.


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Histology_Ross. return as straight vessels toward the base of the pyramid (see G3, Fig. 20.24). Thus, the efferent arterioles from the juxtamedullary glomeruli give rise to vasa recta involved in the countercurrent exchange system and their peritubular capillary network. These vessels are described in the explanation of the countercurrent exchange system (page 721). Generally, venous flow in the kidney follows a reverse course to arterial flow, with the veins running in parallel with the corresponding arteries (see Fig. 20.24). Thus,  Peritubular cortical capillaries drain into interlobular veins, which in turn drain into arcuate veins, interlobar veins, and the renal vein.  The medullary vascular network drains into arcuate veins and so forth.  Peritubular capillaries near the kidney surface and capillaries of the capsule drain into stellate veins (so called for their pattern of distribution when viewed from the kidney surface), which drain into interlobular veins , and so forth.


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Histology_Ross. The kidneys contain two major networks of lymphatic vessels. These networks are not usually visible in routine histologic sections but can be demonstrated by experimental methods. One network is located in the outer regions of the cortex and drains into larger lymphatic vessels in the capsule. The other network is located more deeply in the substance of the kidney and drains into large lymphatic vessels in the renal sinus. There are numerous anastomoses between the two lymphatic networks.


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Histology_Ross. The fibers that form the renal plexus are derived mostly from the sympathetic division of the autonomic nervous system. They cause contraction of vascular smooth muscle and consequent vasoconstriction.  Constriction of the afferent arterioles to the glomeruli reduces the filtration rate and decreases the production of urine.  Constriction of the efferent arterioles from the glomeruli increases the filtration rate and increases the production of urine.  Loss of sympathetic innervation leads to increased urinary output. It is evident, however, that the extrinsic nerve supply is not necessary for normal renal function. Although the nerve fibers to the kidney are cut during renal transplantation, transplanted kidneys subsequently function normally. URETER, URINARY BLADDER, AND URETHRA All excretory passages, except the urethra, have the same general organization.


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Histology_Ross. URETER, URINARY BLADDER, AND URETHRA All excretory passages, except the urethra, have the same general organization. On leaving the collecting ducts at the area cribrosa, the urine enters a series of structures that do not modify it but are specialized to store and pass the urine to the exterior of the body. The urine flows sequentially to a minor calyx, a major calyx, and the renal pelvis, and leaves each kidney through the ureter to the urinary bladder, where it is stored. The urine is finally voided through the urethra. All of these excretory passages, except the urethra, have the same general structures, namely, a mucosa (lined by transitional epithelium), muscularis, and adventitia (or, in some regions, a serosa). Transitional epithelium lines the calyces, ureters, bladder, and the initial segment of the urethra.


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Histology_Ross. Transitional epithelium lines the calyces, ureters, bladder, and the initial segment of the urethra. Transitional epithelium (urothelium) lines the excretory passages leading from the kidney. This stratified epithelium is essentially impermeable to salts and water. The epithelium begins in the minor calyces as two cell layers and increases to an apparent four to five layers in the ureter (Fig. 20.25) and as many as six or more layers in the empty bladder. However, chapter 20 Urinary System U R ETE R, U R I NARY B LADD E R, AN D U R ETH RA 723 FIGURE 20.25 • Photomicrograph of transitional epithelium (urothelium). This H&E–stained specimen shows the 4to 5-celllayer thickness of the epithelium in the relaxed ureter. The surface cells exhibit a rounded or dome-shaped profile. The connective tissue below the epithelium (Ep) is relatively cellular and contains a number of lymphocytes. Blood vessels (BV) are also abundant in this area. 450.


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Histology_Ross. when the bladder is distended, as few as three layers are seen. This change reflects the ability of the cells to accommodate to distension. The cells in the distended bladder, particularly the large surface cells and those in the layers below, flatten and unfold to accommodate the increasing surface area. As the individual cells unfold and flatten, the resulting appearance is the “true” three layers.


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Histology_Ross. In routine histologic sections obtained from the empty bladder, the surface epithelial cells are usually cuboidal and bulge into the lumen. They are frequently described as “dome shaped” or “umbrella” cells because of the curvature of the apical surface (see Fig. 20.25). When examined with the TEM, the plasma membrane exhibits an unusual feature (e.g., modified areas of the plasma membrane called plaques) are seen (Fig. 20.26). These plaques appear to be more rigid and thicker (up to 12 nm) than the rest of the apical plasma membrane. Actin filaments are observed stretching from the inner surface of the plaques into the cytoplasm. In the undistended urinary bladder, the plaques give the luminal surface of cells an irregular scalloped contour (Fig. 20.27). Each cell appears to fold inward on itself. Because of this folding, the plaques appear as a series of fusiform vesicles. Their lumina, however, are in continuity with the cell’s exterior. As the bladder distends, the fusiform


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Histology_Ross. on itself. Because of this folding, the plaques appear as a series of fusiform vesicles. Their lumina, however, are in continuity with the cell’s exterior. As the bladder distends, the fusiform vesicles unfold and become part of the surface as the cell stretches and flattens (Fig. 20.28).


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Histology_Ross. FIGURE 20.26 • Transmission electron micrograph of urinary bladder epithelium. The mucous membrane of the urinary bladder consists of transitional epithelium (Ep) with an underlying lamina propria (LP). The epithelial cells contain unique fusiform vesicles, which are evident here at this relatively low magnification. These are seen at higher magnification in Figure 20.24. 5,000. Smooth muscle of the urinary passages is arranged in bundles. A dense collagenous lamina propria underlies the urothelium throughout the excretory passages. Neither a muscularis mucosae nor a submucosal layer is present in their walls. In the tubular portions (ureters and urethra), usually two layers of smooth muscle lie beneath the lamina propria:  Longitudinal layer, the inner layer that is arranged in a loose spiral pattern Circular layer, the outer layer that is arranged in a tight


Histology_Ross

Histology_Ross. Note that this arrangement of the smooth muscle is opposite that of the muscularis externa of the intestinal tract. The smooth muscle of the urinary passages is mixed with connective tissue, so that it forms parallel bundles rather than pure FIGURE 20.27 • Transmission electron micrograph of the apical portion of a transitional epithelial cell. a. The cytoplasm displays small vesicles, filaments, and mitochondria, but the most distinctive feature of the cell is its fusiform vesicles (FV). 27,000. b. The higher magnification shows that the membrane forming the vesicles appears to be similar to the plasma membrane of the cell surface (arrows). Both membranes are thickened and give the impression of possessing a degree of rigidity greater than that of plasma membrane in other locations. The thickened plasma membrane represents a sectioned view of a surface plaque. The fusiform vesicles are formed by the infolding of the plaques in the cells of the relaxed urinary bladder. 60,000.


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Histology_Ross. muscular sheets. Peristaltic contractions of the smooth muscle move the urine from the minor calyces through the ureter to the bladder. Each ureter conducts urine from the renal pelvis to the urinary bladder and is approximately 24 to 34 cm long. The distal part of the ureter enters the urinary bladder and follows an oblique path through the wall of the bladder. Transitional epithelium (urothelium) lines the luminal surface of the wall of the ureter. The remainder of the wall is composed of smooth muscle and connective tissue. The smooth


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Histology_Ross. FIGURE 20.28 • Diagrams of the luminal surface of transitional epithelial cells. The upper drawing depicts part of a surface cell in a distended bladder; the lower drawing depicts the same cell as it would appear in a relaxed bladder. The plasma membrane is thickened in regions to form plaques. The interplaque regions consist of membrane that is not thickened. In the relaxed bladder, the plaques are invaginated into the cell, and although they retain their continuity with the surface, the invaginated plaques typically appear as isolated fusiform vesicles in electron micrographs. Filaments attached to the undersurface of the plaques may prevent undue stretching in the distended bladder. (Modified from Staehelin LA, Chlapowski FJ, Bonneville MA. Lumenal plasma membrane of the urinary bladder. I. Three-dimensional reconstruction from freeze-etch images. J Cell Biol 1972;53:73–91.) muscle is arranged in three layers: an inner longitudinal layer, a middle circular layer, and an outer


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Histology_Ross. I. Three-dimensional reconstruction from freeze-etch images. J Cell Biol 1972;53:73–91.) muscle is arranged in three layers: an inner longitudinal layer, a middle circular layer, and an outer longitudinal layer (Plate 78, page 736). However, the outer longitudinal layer is present only at the distal end of the ureter. Usually, the ureter is embedded in the retroperitoneal adipose tissue. The adipose tissue, vessels, and nerves form the adventitia of the ureter.


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Histology_Ross. As the bladder distends with urine, the openings of the ureters are compressed, reducing the possibility of reflux of urine into the ureters. Contraction of the smooth muscle of the bladder wall also compresses the openings of the ureters into the bladder. This action helps prevent the spread of infection from the bladder and urethra, frequent sites of chronic infection (particularly in females), to the kidney. In the terminal portion of the ureters, a thick outer layer of longitudinal muscle is present in addition to the two listed above, particularly in the portion of the ureter that passes through the bladder wall. Most descriptions of the bladder musculature indicate that this longitudinal layer continues into the wall of the bladder to form a principal component of its wall. The smooth muscle of the bladder, however, is not as clearly separated into distinctive layers. chapter 20 Urinary System U R ETE R, U R I NARY B LADD E R, AN D U R ETH RA 725


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Histology_Ross. chapter 20 Urinary System U R ETE R, U R I NARY B LADD E R, AN D U R ETH RA 725 The urinary bladder is a distensible reservoir for urine, located in the pelvis, posterior to the pubic symphysis; its size and shape change as it fills. It contains three openings, two for the ureters (ureteric orifces) and one for the urethra (internal urethral orifce). The triangular region defined by these three openings, the trigone, is relatively smooth and constant in thickness, whereas the rest of the bladder wall is thick and folded when the bladder is empty and thin and smooth when the bladder is distended. These differences reflect the embryologic origins of the trigone and the rest of the bladder wall: the trigone is derived from the embryonic mesonephric ducts, and the major portion of the wall originates from the cloaca.


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Histology_Ross. The smooth muscle of the bladder wall forms the detrusor muscle. Toward the opening of the urethra, the muscle fibers form the involuntary internal urethral sphincter, a ringlike arrangement of muscle around the opening of the urethra. The smooth muscle bundles of the detrusor muscle are less regularly arranged than that of the tubular portions of the excretory passages, and thus the muscle and collagen bundles are randomly mixed (Plate 79, page 738). Contraction of the detrusor muscle of the bladder compresses the entire organ and forces the urine into the urethra.


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Histology_Ross. The bladder is innervated by both sympathetic and parasympathetic divisions of the autonomic nervous system:  Sympathetic fbers form a plexus in the adventitia of the bladder wall. These fibers probably innervate blood vessels in the wall.  Parasympathetic fbers originate from S2 to S4 seg ments of the spinal cord and travel with pelvic splanchnic nerves into the bladder. They end in terminal ganglia in the muscle bundles and the adventitia and are the efferent fibers of the micturition refex.  Sensory fbers from the bladder to the sacral portion of the spinal cord are the afferent fibers of the micturition reflex. The urethra is the fibromuscular tube that conveys urine from the urinary bladder to the exterior through the external urethral orifce. The size, structure, and functions of the urethra differ in males and females.


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Histology_Ross. In the male, the urethra serves as the terminal duct for both the urinary and genital systems. It is about 20 cm long and has three distinct segments:  Prostatic urethra extends for 3 to 4 cm from the neck of the bladder through the prostate gland (see page 785). It is lined with transitional epithelium (urothelium). The ejaculatory ducts of the genital system enter the posterior wall of this segment, and many small prostatic ducts also empty into this segment.


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Histology_Ross.  Membranous urethra extends for about 1 cm from the apex of the prostate gland to the bulb of the penis. It passes through the deep perineal pouch of the pelvic floor as it enters the perineum. Skeletal muscle of the deep perineal pouch surrounding the membranous urethra forms the external (voluntary) sphincter of the urethra. Transitional epithelium ends in the membranous urethra. This segment is lined with a stratified or pseudostratified columnar epithelium that resembles the epithelium of the genital duct system more than it resembles the epithelium of the more proximal portions of the urinary duct system.


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Histology_Ross.  Penile (spongy) urethra extends for about 15 cm through the length of the penis and opens on the body surface at the glans penis. The penile urethra is surrounded by the corpus spongiosum as it passes through the length of the penis. It is lined with pseudostratified columnar epithelium except at its distal end, where it is lined with stratified squamous epithelium continuous with that of the skin of the penis. Ducts of the bulbourethral glands (Cowper’s glands) and of the mucus-secreting urethral glands (glands of Littré) empty into the penile urethra.


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Histology_Ross. In the female, the urethra is short, measuring 3 to 5 cm in length from the bladder to the vestibule of the vagina, where it normally terminates just posterior to the clitoris. The mucosa is traditionally described as having longitudinal folds. As in the male urethra, the lining is initially transitional epithelium, a continuation of the bladder epithelium, but changes to stratified squamous epithelium before its termination. Some investigators have reported the presence of stratified columnar and pseudostratified columnar epithelium in the midportion of the female urethra.


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Histology_Ross. Numerous small urethral glands, particularly in the proximal part of the urethra, open into the urethral lumen. Other glands, the paraurethral glands, which are homologous to the prostate gland in the male, secrete into the common paraurethral ducts. These ducts open on each side of the external urethral orifice. They produce an alkaline secretion. The lamina propria is a highly vascularized layer of connective tissue that resembles the corpus spongiosum in the male. Where the urethra penetrates the urogenital diaphragm (membranous part of the urethra), the striated muscle of this structure forms the external (voluntary) urethral sphincter. This page intentionally left blank.


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Histology_Ross. The urinary system consists of the paired kidneys, the paired ureters, which lead from the kidneys to the urinary bladder, and the urethra, which leads from the bladder to the exterior of the body. The kidneys conserve body fluid and electrolytes and remove metabolic wastes such as urea, uric acid, creatinine, and breakdown products of various substances. They produce urine, initially an ultrafiltrate of blood that is modi-fied by selective resorption and specific secretion by kidney tubule cells. The kidneys also function as endocrine organs, producing erythropoi-etin, a growth factor that regulates red blood cell formation, and renin, a hormone involved in blood pressure and blood volume control. They also hydroxylate vitamin D, a steroid prohormone, to produce its active form. Each kidney is a flattened, bean-shaped structure approximately 10 cm long, 6.5 cm wide (from convex to concave border), and 3 cm thick. The concave medial border of each kidney contains a hilum, an indented


Histology_Ross

Histology_Ross. is a flattened, bean-shaped structure approximately 10 cm long, 6.5 cm wide (from convex to concave border), and 3 cm thick. The concave medial border of each kidney contains a hilum, an indented region through which blood vessels, nerves, and lymphatic vessels enter and leave the kidney. The funnel-shaped origin of the ureter, the renal pelvis, also leaves the kidney at the hilum. A cut, hemi-sected fresh kidney reveals two distinct regions: a cortex, the reddish-brown outer region, and a medulla, a much lighter inner part continu-ous with the renal pelvis. The cortex is characterized by renal corpuscles and their tubules, including the convoluted and straight tubules of the nephron, the collecting tubules, and an extensive vascular supply.


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Kidney, human, fresh specimen ×3.

Histology_Ross. Kidney, human, fresh specimen ×3.


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Histology_Ross. A frontal section through the cortex and medulla of an unembalmed kidney obtained from autopsy is shown here. The visible hilar region consists of minor calyces (grey/white) surrounded by yellow in appearance adipose tissue. The outer part of the kidney has a reddish-brown appearance; this is the cortex. It is easily distinguished from the inner portion, the medulla, which is further divided into an outer portion (OM), identified here by the presence of straight blood vessels, the vasa recta (VR), and an inner portion (IM), which has a lighter and more homogenous appearance. The medulla consists of renal pyramids, which have their base facing the cortex and their apex in the form of a papilla (P) is directed towards the hilum. The pyramids are separated, sometimes only partially as in this figure, by cortical material that is designated the renal columns (RC). The majority of the outer part of the pyramid on the left, has not been included in the plane of


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Histology_Ross. Cortex and medulla, kidney, human, H&E ×20. A histologic section including the cortex and part of the medulla is shown here. Located at the boundary between the two (partly marked by the dashed line) are numerous profiles of arcuate arteries (AA) and arcuate veins (AV ). The most distinctive feature of the renal cortex, regardless of the plane of section, is the presence of the renal corpuscles (RC). These are spherical structures composed of a glomerulus (glomerular vascular tuft) surrounded by the visceral the section. The papillae are free tips of the pyramids that project into the first of a series of large urine collecting spaces referred to as the minor calyces (MC); the inner surface of the calyx is white. The minor calyces drain into major calyces, and in turn, these open into the renal pelvis, which funnels urine into the ureter.


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Histology_Ross. An interesting feature in this specimen is that the blood has been retained in many of the vessels, thereby allowing for visualization of several renal vessels in their geographic location. Among the vessels that can be identified in the cut face of the kidney shown here are the interlobular vessels (IV) within the cortex; the arcuate veins (AV) and the arcuate arteries (AA) at the base of the pyramids; the interlobar arteries (ILA) and veins (ILV) between renal pyramids and, in the medulla, the vessels going to and from the capillary network of the pyramid. The latter vessels, both arterioles and venules, are relatively straight and are designated collectively as the vasa recta (VR). (Specimen courtesy of Dr. Eric A. Pfeifer, Mayo Clinic, Rochester, MN).


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Histology_Ross. and parietal epithelium of Bowman’s capsule. Also seen in the cortex are groups of tubules that are more or less straight and disposed in a radial direction from the base of the medulla (arrows); these are the medullary rays. In contrast, the medulla presents profiles of tubular structures that are arranged as gentle curves in the outer part of the medulla, turning slightly to become straight in the inner part of the medulla. The disposition of the tubules (and blood vessels) gives the cut face of the pyramid a slightly striated appearance that is also evident in the gross specimen (see figure above). KEY AA, arcuate arteries AV, arcuate veins ILA, Interlobar artery ILV, Interlobar vein IM, inner medulla IV, interlobular vessels MC, minor calyx OM, outer medulla P, papilla RCol, renal column RC, renal corpuscles VR, vasa recta arrows, medullary rays dashed line, boundary between cortex and medulla


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Histology_Ross. The nephron is the functional unit of the kidney. There are about 2 million nephrons in each human kidney. They are responsible for the production of urine and correspond to the secretory part of other glands. The collecting tubules, responsible for the final concentration of the urine, are analogous to the ducts of exocrine glands. The nephron is made up of the renal corpuscle and the renal tubule. The renal corpuscle consists of the glomerulus, a tuft of 10 to 20 capillary loops, surrounded by a double-layered epithelial cup, the renal or Bowman’s capsule. The glomeru-lar capillaries are supplied at the vascular pole of Bowman’s capsule by an afferent arteriole and drained by an efferent arteriole that leaves Bow-man’s capsule at the vascular pole and then branches to form a new capillary network to supply the kidney tubules. The opposite pole of Bowman’s capsule, the urinary pole, is where the filtrate leaves the renal capsule. The tubular parts of the nephron are the proximal


Histology_Ross

Histology_Ross. network to supply the kidney tubules. The opposite pole of Bowman’s capsule, the urinary pole, is where the filtrate leaves the renal capsule. The tubular parts of the nephron are the proximal thick segment (consisting of the proximal convoluted tubule and the proximal straight tubule), the thin segment, which constitutes the thin limb of the loop of Henle, and the distal thick segment, consisting of the distal straight tubule and the distal convoluted tubule. The loop of Henle is the U-shaped portion of the nephron consisting of the thick straight portions of the proximal and distal tubules and the thin segment between them. The distal convoluted tubule joins the collecting tubule. The nephron and the collecting tubule constitute the uriniferous tubule.


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Cortex, kidney, human, H&E ×60.

Histology_Ross. Cortex, kidney, human, H&E ×60.


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Histology_Ross. The renal cortex can be divided into regions referred to as the cortical labyrinth (CL) and the medullary rays (MR). The cortical labyrinth contains the renal corpuscles (RC ), which appear as relatively large spherical structures. Surrounding each renal corpuscle are the proximal and distal convoluted tubules. They are also part of the cortical labyrinth. The convoluted tubules, particularly the proximal, because of their tortuosity, present a variety of profiles, most of which are oval or circular; others, more elongate, are in the shape of a letter J, a C, or even an S. The medullary rays are composed of groups of straight tubules oriented in the same direction and appear to radiate from the base of the pyramid. When the medullary rays are cut longitudinally, as they are in this figure, the tubules present elongated profiles. The medullary rays contain proximal straight tubules (thick segments; descending limb of Henle’s loop), distal straight tubules (thick segments; ascending


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Histology_Ross. the tubules present elongated profiles. The medullary rays contain proximal straight tubules (thick segments; descending limb of Henle’s loop), distal straight tubules (thick segments; ascending limbs of Henle’s loop), and collecting tubules.


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Histology_Ross. Cortex, kidney, human, H&E ×120. This figure presents another profile of the renal cortex, at a somewhat higher magnification, cut in a plane at a right angle to the section in figure above. The peripheral part of the micrograph shows the cortical labyrinth in which the tubules display chiefly round and oval profiles but also some that are more elongate and curved. The appearance is the same as the cortical labyrinth areas of figure above. A renal corpuscle (RC) is also present in the cortical labyrinth. In contrast, the profiles presented by the tubules of the medullary ray in this figure are quite different from those seen in figure above. All of the tubules bounded by the dashed line belong to the medullary ray (MR), and all are cut in cross section.


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Histology_Ross. A general survey of the tubules within the medullary ray reveals that several distinct types can be recognized on the basis of the size of the tubule, shape of the lumen, and size of the tubule cells. These features as well as those of the cortical labyrinth are considered in Plate 76. PLATE 75 KEY CL, cortical labyrinth MR, medullary ray RC, renal corpuscle dashed line, approximate boundary of the medullary ray


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Histology_Ross. Proximal and distal convoluted tubules display features that aid in their identification in H&E-stained paraffin sections. Proximal convoluted tubules generally have a larger diameter than distal tubules have; cross sections of the lumen often appear stellate. A brush border (apical microvilli) is often visible on the proximal tubule cells. Also, the proximal convoluted tubule is more than twice as long as the distal convo-luted tubule; thus, the majority of tubular profiles in the cortical labyrinth will be of proximal tubules. Mesangial cells and their extracellular matrix constitute the mesangium of the renal corpuscle. They underlie the endothelium of the cap-illaries of the glomerular tuft and extend to the vascular pole, where they become part of the juxtaglomerular apparatus. The terminal portion of the distal thick segment of the nephron lies close to the afferent arteriole. Tubule epithelial cells closest to the arteriole are thinner, taller, and more closely packed than


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Histology_Ross. terminal portion of the distal thick segment of the nephron lies close to the afferent arteriole. Tubule epithelial cells closest to the arteriole are thinner, taller, and more closely packed than other tubule cells and constitute the macula densa. Arterial smooth muscle cells opposite the macula densa are modified into juxtaglomerular cells that secrete renin in response to decreased blood NaCl concentration.


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Histology_Ross. Proximal and distal convoluted tubules, kidney, human, H&E ×240. In this figure, an area of cortical labyrinth, there are six distal convoluted tubule (DC) profiles. The proximal convoluted tubules (unlabeled) have a slightly larger outside diameter than the distal tubules have. The proximal tubules have a brush border, whereas the distal tubules have a cleaner, sharper luminal Renal corpuscles, kidney, human, H&E ×360. The renal corpuscle appears as a spherical structure whose periphery is composed of a thin capsule that encloses a narrow clear-appearing space, the urinary space (asterisks), and a capillary tuft or glomerulus that appears as a large cellular mass. The capsule of the renal corpuscle, known as the renal or


Histology_Ross

Histology_Ross. Bowman’s capsule, actually has two parts: a parietal layer, which is marked (BC ), and a visceral layer. The parietal layer consists of simple squamous epithelial cells. The visceral layer consists of cells, called podocytes (Pod ), that lie on the outer surface of the glomerular capillary. Except where they clearly line the urinary space, as the labeled cells do in figure on left, podocytes may be difficult to distinguish from the capillary endothelial cells. To complicate matters, the mesangial cells are also a component of the glomerulus. In general, nuclei of podocytes are larger and stain less intensely than do the endothelial and mesangial cell nuclei. surface. The lumen of the proximal tubules is often star shaped; this is not the case with distal tubules. Typically, fewer nuclei appear in a cross section of a proximal tubule than in an equivalent segment of a distal tubule.


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Histology_Ross. Most of the above points can also be utilized in distinguishing the straight portions of the proximal and distal thick segments in the medullary rays, as shown in figure on right. Proximal and distal straight tubules, kidney, human, H&E ×240. In this figure, all of the tubular profiles within the medullary ray are rounded except for a proximal convoluted tubule (PC) included in the lower right corner of the figure (it belongs to the adjacent cortical labyrinth). Second, the number of proximal straight (P) and distal straight (D) tubular profiles are about equal in the medullary ray, as is shown by the labeling of each tubule in this figure. Note that, in contrast to the distal straight tubules, the proximal straight tubules display a brush border and have a larger outside diameter, with many displaying a star-shaped lumen. The medullary ray also contains collecting tubules (CT ). They are considered in Plate 77.


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Histology_Ross. A distal (DC) and two proximal (PC) convoluted tubules are marked in figure on left. The cells of the distal tubule are more crowded on one side. These crowded cells constitute the macula densa (MD) that lies adjacent to the afferent arteriole. In figure on right, both the vascular pole and the urinary pole of the renal corpuscle are evident. The vascular pole is characterized by the presence of arterioles (A), one of which is entering or leaving (double-headed arrow) the corpuscle. The afferent arteriole possesses modified smooth muscle cells with granules, the juxtaglomerular cells (not evident in this figure). At the urinary pole, the parietal layer of Bowman’s capsule is continuous with the beginning of the proximal convoluted tubule (PC ). Here, the urinary space of the renal corpuscle continues into the lumen of the proximal tubule, and the lining cells change from simple squamous to simple cuboidal or low columnar with a brush border.


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Histology_Ross. KEY A, arteriole BC, Bowman’s capsule (parietal layer) CT, collecting tubule D, distal straight tubule DC, distal convoluted tubule MD, macula densa P, proximal (straight tubule) PC, proximal convoluted tubule Pod, podocyte (visceral layer of Bowman’s capsule) asterisks, urinary space double-headed arrow, blood vessel at vascular pole of renal corpuscle Renal corpuscles are restricted to the cortical labyrinth. The medulla contains the thick straight segments of proximal and distal tubules, along with their thin segments, the collecting tubules and ducts, and the blood vessels that run in parallel with them. These structures function as the countercurrent multiplier and countercurrent exchange systems that, ultimately, produce hypertonic urine. The final urine drains from the papillary ducts (of Bellini) into calyces that then empty into the renal pelvis. Medulla, kidney, human, H&E ×240.


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Histology_Ross. A section through the outer portion of the medulla is shown in this figure. This region contains proximal and distal thick segments, thin segments, and collecting tubules. All of the tubules are parallel, and all are cut in cross section; thus, they present circular profiles. The proximal straight tubules (P) display typical star-shaped lumina and a brush border (or the fragmented apical cell surface from which the brush border has been partially broken). These tubules have outside diameters that are generally larger than those of 734 the distal straight tubules (D). As mentioned previously and as shown here, the distal straight tubules display a larger number of nuclei than do comparable segments of proximal straight tubule cells. Note, also, that the lumen of the distal tubule is more rounded and the apical surface of the cells is sharper. The collecting tubules (CT ) have outer diameters that are about the same as those of the proximal tubules and larger than those of distal


Histology_Ross

Histology_Ross. more rounded and the apical surface of the cells is sharper. The collecting tubules (CT ) have outer diameters that are about the same as those of the proximal tubules and larger than those of distal tubules. The cells forming the collecting tubules are cuboidal and smaller than those of proximal tubules; thus, they also display a relatively larger number of nuclei than do comparable segments of proximal tubule cells. Count them! Finally, boundaries between the cells that constitute the collecting tubules are usually evident (asterisks); this serves as one of the most dependable features for the identification of collecting tubules.


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Histology_Ross. The thin segments (T ) have the thinnest walls of all renal tubules seen in the medulla. They are formed by a low cuboidal or simple squamous epithelium, as seen here, and the lumina are relatively large. Occasionally, a section includes the region of transition from a thick to a thin segment and can be recognized even in a cross section through the tubule. One such junction is evident in this figure (the tubule with two arrows in the lumen). On one side, the tubule cell (left-pointing arrow) is characteristic of the proximal segment; it possesses a distinctive brush border. The other side of the tubule (right-pointing arrow) is composed of low cuboidal cells that resemble the cells forming the thin segments. In addition to the renal and collecting tubules, there are many other small tubular structures in this figure. Thin-walled and lined by endothelium, they are small blood vessels. Renal pyramid, kidney, human, H&E ×20.


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Histology_Ross. Renal pyramid, kidney, human, H&E ×20. This figure shows a renal pyramid at low magnification. The pyramid is a conical structure composed principally of medullary straight tubules, ducts, and the straight blood vessels (vasa recta). The dashed line at the left of the micrograph is placed at the junction between cortex and medulla; thus, it marks the base of the pyramid. Note the arcuate vessels (AV ) that lie at the boundary of cortex and medulla. They define the boundary line. The few renal corpuscles (RC), upper left, belong to the renal column of the medulla. They are referred to as juxtamedullary corpuscles. The pyramid is somewhat distorted in this specimen, as evidenced by regions of longitudinally sectioned tubules, lower left, and cross-sectioned and obliquely sectioned tubules in other regions. In effect, part of the pyramid was bent, thus the change in the plane of section of the tubules.


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Histology_Ross. The apical portion of the pyramid (arrowhead), known as the renal papilla, is lodged in a cupor funnel-like structure referred to as the calyx. It collects the urine that leaves the tip of the papilla from the papillary ducts (of Bellini). (The actual tip of the papilla is not seen within the plane of section, nor are the openings of the ducts at this low magnification.) The surface of the papilla that faces the lumen of the minor calyx is simple columnar or cuboidal epithelium (SCEp). (In places, this epithelium has separated from the surface of the papilla and appears as a thin strand of tissue.) The calyx is lined by transitional epithelium (TEp). Although not evident at the low magnification shown here, the boundary between the columnar epithelium covering the papilla and the transitional epithelium covering the inner surface of the calyx is marked by the diamonds.


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Histology_Ross. KEY AV, arcuate vessels CT, collecting tubules D, distal straight tubule P, proximal straight tubule RC, renal corpuscle SCEp, simple columnar epithelium T, thin segment TEp, transitional epithelium arrowhead, location of apex of pyramid asterisks, boundaries between cells of a collecting tubule diamonds, boundary between a transitional and a columnar epithelium left-pointing arrow, proximal tubule cell right-pointing arrow, thin segment cell


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Histology_Ross. PLATE 78 • URETER The ureters are paired tubular structures that convey urine from the kid-neys to the urinary bladder. They are lined with transitional epithelium (urothelium), an impervious layer that lines the urinary excretory passa-ges from the renal calyces through the urethra. The ability of this epithe-lium to become thinner and flatter allows all of these passages to accommodate to distension by the urine. The epithelium rests on a dense collagenous lamina propria, which in turn, rests on an inner longitudinal and an outer circular layer of smooth muscle. Regular peristaltic contractions of this muscle contribute to the flow of urine from the kidney to the urinary bladder. ORIENTATION MICROGRAPH: As shown in this low-power orienta-tion micrograph, the wall of the ureter consists of a mucosa (Muc), a muscularis (Mus), and an adventitia (Adv). Note that the ureters are lo-cated behind the peritoneum of the abdominal cavity in their course to the bladder. Thus, a serosa (Ser)


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Histology_Ross. of a mucosa (Muc), a muscularis (Mus), and an adventitia (Adv). Note that the ureters are lo-cated behind the peritoneum of the abdominal cavity in their course to the bladder. Thus, a serosa (Ser) may be found covering a portion of the circumference of the tube. Also, because of contraction of the smooth muscle of the muscularis, the luminal surface is characteristically folded, thus creating a star-shaped lumen. ATATAT BVBVBV AdvAdvAdv MucMucMuc MusMusMus Ser


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Histology_Ross. Ureter, monkey, H&E ×160. The wall of the ureter from the rectangular area in the orientation micrograph is examined at higher magnification in this figure. One can immediately recognize the thick epithelial lining, which appears distinct and sharply delineated from the remainder of the wall. This is the transitional epithelium (urothelium), (Ep). The remainder of the wall is made up of connective tissue (CT ) and smooth muscle. The latter can be recognized as the darker-staining layer. The section also shows some adipose tissue (AT ), a component of the adventitia. The transitional epithelium and its supporting connective tissue constitute the mucosa (Muc). A distinct submucosa is not present, although the term is sometimes applied to the connective tissue that is closest to the muscle.


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Histology_Ross. The muscularis (Mus) is arranged as an inner longitudinal layer (SM(l)), a middle circular layer (SMc), and an outer longitudinal layer (SM(l)). However, the outer longitudinal layer is present only at the lower end of the ureter. In a cross section through the ureter, the inner and outer smooth muscle layers are cut in cross section, whereas the middle circular layer of the muscle cells is cut longitudinally. This is as they appear in this figure. Transitional epithelium, ureter, monkey, H&E ×400.


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Histology_Ross. Transitional epithelium, ureter, monkey, H&E ×400. This figure shows the inner longitudinal smooth muscle layer (SM(l)) at higher magnification. Note that the nuclei appear as round profiles, indicating that the muscle cells have been cross-sectioned. This figure also shows the transitional epithelium (Ep) to advantage. The surface cells of the transitional epithelium (urothelium) are characteristically the largest, and some are binucleate (arrow). The basal cells are the smallest, and typically, the nuclei appear crowded because of the minimal cytoplasm of each cell. The intermediate cells appear to consist of several layers and are composed of cells larger in size than the basal cells but smaller than the surface cells. KEY Adv, adventitia AT, adipose tissue BV, blood vessels CT, connective tissue Ep, transitional epithelium Muc, mucosa Mus, muscularis Ser, serosa SM(c), circular layer of smooth muscle SM(l), longitudinal layer of smooth muscle arrow, binucleate surface cell


Histology_Ross

Histology_Ross. The urinary bladder receives the urine from the two ureters and stores it until neural stimulation causes it to contract and expel the urine via the urethra. It, too, is lined with transitional epithelium (urothelium). Beneath the epithelium and its underlying con-nective tissue, the wall of the urinary bladder contains smooth muscle that is usually described as being arranged as an inner longitudinal layer, a middle circular layer, and an outer longitudinal layer. As in most distensible hollow viscera that empty their con-tents through a narrow aperture, the smooth muscle in the wall of the urinary bladder is less regularly arranged than the description indicates, allowing contraction to re-duce the volume relatively evenly throughout the bladder. ORIENTATION MICROGRAPH: This orientation micrograph of the urinary blad-der reveals the full thickness of the bladder wall. The luminal surface epithelium is at the top of the micrograph. One of the ureters can be seen as it passes through


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Histology_Ross. micrograph of the urinary blad-der reveals the full thickness of the bladder wall. The luminal surface epithelium is at the top of the micrograph. One of the ureters can be seen as it passes through the bladder wall to empty its contents into the bladder lumen. Most of the tissue to the sides and below the ureteral profile is smooth muscle.


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Histology_Ross. Urinary bladder, human, H&E ×60. This micrograph shows most of the entire thickness of the urinary bladder. An unusual feature is the presence of one of the ureters (U ) as it is passing through the bladder wall to empty its contents into the bladder lumen. The transitional epithelium (Ep) lining the bladder is seen on the right. Beneath the epithe lium is a relatively thick layer of connective tissue (CT ) containing blood vessels (BV ) of various sizes. Note that the connective tissue stains more eosinophilic than the smooth muscle of the underlying muscularis (M). The epithelium and connective tissue constitute the mucosa of the bladder. The muscularis consists of smooth muscle arranged in three indistinct layers. It should be noted that as the ureter passes through the bladder wall, it carries with it a layer of longitudinally oriented smooth muscle (SM(L)). Medium-size arteries (A) and veins (V ) are occasionally seen in the muscularis.


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Histology_Ross. Transitional epithelium, urinary bladder, human, H&E ×250. This higher magnification of the left rectangle of figure above shows the transitional epithelium (Ep) and the underlying connective tissue (CT ) that represent the mucosa of the ureter. Adjacent to the mucosa are bundles of longitudinally sectioned smooth muscle (SM(L)) that belong to the ureter. A small lymphatic vessel (Lym) is present in the connective tissue adjacent to the smooth muscle. Note the lymphocytes, identified by their small round densely stained nuclei, within the lumen of the vessel. Transitional epithelium, urinary bladder, human, H&E ×250.


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Histology_Ross. Transitional epithelium, urinary bladder, human, H&E ×250. This higher magnification of the right rectangle of figure above shows the bladder transitional epithelium (Ep) and the underlying connective tissue (CT ) of the bladder wall. The transitional epithelium is often characterized by the presence of surface cells that exhibit a “dome” shape. In addition, many of these cells are binucleate (arrows). The thickness of transitional epithelium is variable. When the bladder is fully distended, as few as three cell layers are seen. Here, in the contracted bladder, it appears that there are as many as ten cell layers, a result of the cells folding over one another as the smooth muscle contracts and the lining surface is reduced. The connective tissue consists of bundles of collagen fibers interspersed with varying numbers of lymphocytes identified by their densely stained round nuclei. A vein (V ) filled with red blood cells is also evident in the mucosal connective tissue.


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Histology_Ross. KEY A, artery BV, blood vessel CT, connective tissue Ep, transitional epithelium Lym, lymphatic vessel M, muscularis SM(L), longitudinally cut smooth muscle U, ureter V, vein arrows, binucleate cells


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Histology_Ross. OVERVIEW OF THE ENDOCRINE SYSTEM / 740 Hormones and Their Receptors / 740 Regulation of Hormone Secretion and Feedback Mechanism / 742 PITUITARY GLAND (HYPOPHYSIS) / 742 Gross Structure and Development / 743 Blood Supply / 743 Nerve Supply / 745 Structure and Function of the Pituitary Gland / 745 Anterior Lobe of the Pituitary Gland (Adenohypophysis) / 745 Posterior Lobe of the Pituitary Gland (Neurohypophysis) / 748 HYPOTHALAMUS / 751 PINEAL GLAND / 752 THYROID GLAND / 755 PARATHYROID GLANDS / 760 ADRENAL GLANDS / 762 Blood Supply / 762 Cells of the Adrenal Medulla / 764 Zonation of the Adrenal Cortex / 766 Zona Glomerulosa / 766 Zona Fasciculata / 767 Zona Reticularis / 768 Fetal Adrenal Gland / 768 Folder 21.1 Functional Considerations: Regulation of Pituitary Gland Secretion / 743 Folder 21.2 Clinical Correlation: Principles of Endocrine Diseases / 750 Folder 21.3 Clinical Correlation: Pathologies Associated with ADH Secretion / 753 Folder 21.4 Clinical Correlation: Abnormal


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Histology_Ross. Folder 21.2 Clinical Correlation: Principles of Endocrine Diseases / 750 Folder 21.3 Clinical Correlation: Pathologies Associated with ADH Secretion / 753 Folder 21.4 Clinical Correlation: Abnormal Thyroid Function / 758 Folder 21.5 Clinical Correlation: Chromaffin Cells and Pheochromocytoma / 766 Folder 21.6 Functional Considerations: Biosynthesis of Adrenal Hormones / 769


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Histology_Ross. The endocrine system produces various secretions called hormones [Gr. hormaein, to set in motion] that serve as effectors to regulate the activities of various cells, tissues, and organs in the body. Its functions are essential in maintaining homeostasis and coordinating body growth and development and are similar to that of the nervous system: Both communicate information to peripheral cells and organs. Communication in the nervous system is through transmission of neural impulses along nerve cell processes and the discharge of neurotransmitter. Communication in the endocrine system is through hormones, which are carried to their destination via connective tissue spaces and the vascular system. These two systems are functionally interrelated. The endocrine system produces a slower and more prolonged response than the nervous system. Both systems may act simultaneously on the same target cells and tissues, and some nerve cells secrete hormones.


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Histology_Ross. In general, a hormone is described as a biologic substance acting on specific target cells. In the classic definition, a hormone is a secretory product of endocrine cells and organs that passes into the circulatory system (bloodstream) for transport to target cells. For years this endocrine control of target tissues became a central part of endocrinology. Recent research shows that a variety of hormones and hormonally active substances are not always FIGURE 21.1 • Hormonal control mechanisms. This schematic diagram shows three basic types of control mechanisms. a. In endocrine control, the hormone is discharged from a cell into the bloodstream and is transported to the effector cells. b. In paracrine control, the hormone is secreted from one cell and acts on adjacent cells that express specific receptors. c. In autocrine control, the hormone responds to the receptors located on the cell that produces it.


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Histology_Ross. discharged into the bloodstream but are released into connective tissue spaces. They may act on adjacent cells or diffuse to nearby target cells that express specific receptors for that particular hormone. This type of hormonal action is referred to as paracrine control. In addition, some cells express receptors for hormones that they secrete. This type of hormonal action is referred to as autocrine control. These hormones regulate the cell’s own activity. Figure 21.1 summarizes various hormonal control mechanisms. Hormones include three classes of compounds.


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Histology_Ross. Hormones include three classes of compounds. Cells of the endocrine system release more than 100 hormones and hormonally active substances that are chemically divided into three classes of compounds:  Steroids, cholesterol-derived compounds, are synthesized and secreted by cells of the ovaries, testes, and adrenal cortex. These hormones (gonadal and adrenocortical steroids) are released into the bloodstream and transported to target cells with the help of plasma proteins or specialized carrier proteins such as androgen-binding protein. Hormone-binding carrier proteins protect the hormone from degradation during transport to the target tissue. When needed, the hormone is released from the carrier protein to become active.


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Histology_Ross.  Small peptides, polypeptides,and proteins are synthesized and secreted by cells of the hypothalamus, pituitary gland, thyroid gland, parathyroid gland, pancreas, and scattered enteroendocrine cells of the gastrointestinal tract and respiratory system. This group of hormones (e.g., insulin, glucagon, growth hormone [GH], adreno corticotropic hormone [ACTH], follicle-stimulating hormone [FSH], luteinizing hormone [LH], antidiuretic hormone [ADH], oxytocin, interleukins, and various growth factors), when released into the circulation, dissolve readily in the blood and generally do not require special transport proteins. However, most if not all polypeptides and proteins have specific carrier proteins (e.g., insulin growth factor–binding protein (IGFBP).


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Histology_Ross.  Amino acids and arachidonic acid analogs, and their derivatives, including the catecholamines (norepinephrine and epinephrine–phenylalanine/tyrosine derivatives) and prostaglandins, prostacyclins, and leukotrienes (arachidonic acid derivatives). They are synthesized and secreted by many neurons as well as a variety of cells including cells of the adrenal medulla. Also included in this group of compounds are thyroid hormones, the iodinated derivatives of the amino acid tyrosine that are synthesized and secreted by the thyroid gland. When released into the circulation, catecholamines dissolve readily in the blood, in contrast to thyroid hormones that bind to the prealbumin fraction of serum proteins (transthyretin) and a specialized thyroxin-binding protein. Hormones interact with specific hormone receptors to alter biologic activity of the target cells.


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Histology_Ross. The first step in hormone action on a target cell is its binding to a specifc hormone receptor. However, recent studies suggest that some hormones are involved in non–receptor-mediated responses. Hormones interact with their receptors exposed on the surface of the target cell or within its cytoplasm or nucleus. In general, two groups of hormone receptors have been identified:  Cell surface receptors interact with peptide hormones or catecholamines that are unable to penetrate the cell membrane. Activation of these receptors as a result of hormone binding rapidly generates large quantities of small intracellular molecules called second messengers. These molecules amplify the signal initiated by hormone–receptor interaction and are produced by activation of membrane-associated G proteins. Examples of such systems include the adenylate cyclase/cyclic adenosine monophosphate (cAMP) system (for most protein hormones and catecholamines), the guanylyl cyclase/cyclic guanosine monophosphate


Histology_Ross

Histology_Ross. Examples of such systems include the adenylate cyclase/cyclic adenosine monophosphate (cAMP) system (for most protein hormones and catecholamines), the guanylyl cyclase/cyclic guanosine monophosphate (cGMP) system (an antagonistic system for action of cAMP in some protein hormones), the tyrosine kinase system (for insulin and epidermal growth factor [EGF]), the phosphatidylinositol system (for certain hormones such as oxytocin, gonadotropinreleasing hormone [GnRH], angiotensin II, and neurotransmitters such as epinephrine), and activation of ion channels (as with most neurotransmitters). The majority of second messenger molecules exert a stimulatory function on cell metabolism. Examples of second messenger molecules include cAMP, 1,2-diacylglycerol (DAG), inositol 1,4,5-triphosphate (IP3), and Ca2. An inhibitory response is mainly achieved by cGMP, which interferes with the production of cAMP. The second-messenger molecules produced in the cascade reactions of these systems alter the


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Histology_Ross. and Ca2. An inhibitory response is mainly achieved by cGMP, which interferes with the production of cAMP. The second-messenger molecules produced in the cascade reactions of these systems alter the cell’s metabolism and produce hormone-specific responses (Fig. 21.2).