Epigenetics of CKD-MBD

Main Article Content

Taketo Uchiyama Ichiro Ohkido Masataka Okabe Takashi Yokoo


Chronic kidney disease (CKD) is a global epidemic and public health crisis, and one-tenth of the world’s population is affected by CKD. In particular, CKD related to cardiovascular disease; therefore, it is important to suppress the progression of CKD. CKD-mineral and bone disorder (CKD-MBD) is not limited to abnormalities in the serum parameters concerning mineral homeostasis; importantly, it is strongly associated with higher rates of both all-cause and cardiovascular-related mortality. Therefore, CKD-MBD immediate countermeasures.

Epigenetics has been recently recognized as an essential mechanism for pathogenesis in many diseases, including kidney diseases. Epigenetic modifications are inherited nuclear characteristics, or molecular changes that can affect gene expression without altering DNA sequences, including DNA methylation, histone modification, and non-coding RNAs. Epigenetic modifications in patients with acute kidney injury (AKI) or CKD are actively undergoing investigation; however, there have been few reports relating epigenetic changes to mineral homeostasis and CKD-MBD, particularly in the text of parathyroid diseases.

In this review, we first describe epigenetic modification and subsequently discuss the roles and mechanisms of epigenetic modification in the pathogeneses of AKI, AKI-to-CKD transition, CKD, and CKD-MBD.

Article Details

How to Cite
UCHIYAMA, Taketo et al. Epigenetics of CKD-MBD. Medical Research Archives, [S.l.], v. 7, n. 1, jan. 2019. ISSN 2375-1924. Available at: <https://journals.ke-i.org/index.php/mra/article/view/1892>. Date accessed: 27 may 2019. doi: https://doi.org/10.18103/mra.v7i1.1892.
Review Articles


1. Waddington CH. The epigenotype. Endeavour 1942; 1: 18-20.
2. Waddington CH. Genetic assimilations of the bithorax phenotype. Evolution 1956; 10: 1-13
3. Waddington CH. Ultrastructure aspects of cellular differentiation. Symp Soc Exp Biol. 1963; 17: 85-97.
4. Goldberg AD, Allis D, Bernstein E, Epigenetics: A landscape takes shape. Cell 2007; 128: 635-638.
5. Rivera CM, Ren B, Mapping human epigenomes. Cell 2013; 155: 39-55.
6. Guo H, Zhu P, Qiao J, The DNA methylation landscape of human early embryos. Nature 2014; 511: 606-610.
7. Weksberg R, Smith AC, Sadowski P, Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet. 2003; 1: R61-R68.
8. Hitchins MP, Stanier P, Moore GE, Silver-Rusesell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions. J Med Genet. 2001; 38: 810-819.
9. Kamnasaran D, Cox DW, Current status of human chromosome 14. J Med Genet. 2002; 39: 81-90.
10. Nicholls RD, Knepper JL, Genome organization, function, and imprinting in Parader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001; 2: 153-175.
11. Feinberg AP, Vogelstein B, Hypomethylation distinguishes gene of some human cancers from their normal counterparts. Nature 1983; 301: 89-92.
12. Sharma S, Kelly TK, Jones PA, Epigenetics in cancer. Carcinogenesis 2010; 31: 27-36.
13. Jones PA, Baylin SB, The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3: 415-428.
14. Saito Y, Jones PA, Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 2006; 5: 2220-2222.
15. Maciejewska-Rodrigues H, Karouzakis E, Jungel A, Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J Autoimmun. 2010; 35: 15-22.
16. Zhang Z, Song L, Sullivan KE, Global H4 acethylation analysis by ChIP-chip in systemic lupus erythematousus monocytes. Genes Immun. 2010; 11: 124-133.
17. Mutskov V, Felsenfeld G, The human insulin gene is part of a large open chromatin domain specific for human islets. Proc Natl Acad Sci U S A. 2009; 106: 17419-17424.
18. Mu S, Schimosawa T, Fujita T, Epigenetic modulation of renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med. 2011; 17: 573-580
19. Boland MJ, Nazor KL, Loring JF, Epigenetic regulation of pluripotency and differentiation. Circ Res. 2014; 115: 311-324.
20. Trerotola M, Relli V, Alberti S, Epigenetic inheritance and the missing heritability. Hum Genom. 2015; 28, 9-17.
21. Bunkar N, Pathak N, Mishra PK, A key paradigm in reproductive health. Clin Exp Repord Med. 2016; 43: 59-81.
22. Perna AF, Ingrosso D, De Santo NG, Mebrane protein damage and methylation reactions in chronic renal failure. Kidney Int. 1996; 50: 358-366.
23. Robertson KD, Wolffe AP, DNA methylation in health and disease. Nat Rev Genet. 2000; 1: 11-19.
24. Luch A, Nature and nurture-lessons from chemical carcinogenesis. Nat Rev Cancer 2005; 5: 113-125.
25. Ingrosso D, Cimmino A, De Santo NG, Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 2003; 361: 1693-1699.
26. Ptak C, Petronis A, Epigenetics and complex disease: From etiology to new therapeutics. Annu Rev Pharmacol Toxicol. 2008; 48: 257-276.
27. Ympa YP, Sakr Y, Vincent JL, Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med. 2005; 118: 827-832.
28. Basile DP, Nangaku M, Ronco C, Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol. 2016; 27: 687-697.
29. Fontecha-Barriuso M, Ortiz A, Sanz AB, Targeting epigenetic DNA and histone modifications to treat kidney disease. Nephrol Dial Transplant. 2018; 1-12.
30. Allison SJ, Genetic engineering: Trans-epigenetic modulation of target genes in acute kidney injury. Nat Rev Nephrol. 2018; 14: 72.
31. Huang N, Tan L, Qang H, Reduction of DNA hydroxymethylation in the mouse kidney insulted by ischemia reperfusion. Biochem Biophys Res Commun. 2012; 422: 697-702.
32. Guo C, Pei L, Dong Z, DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8. Kidney Int. 2017; 92: 1194-1205.
33. Mimura I, Kanki Y, Nangaku M, Revolution of nephrology research by deep sequencing: ChIP-seq and RNA-seq. Kidney Int. 2014; 85: 31-38.
34. Marumo T, Hishikawa K, Fujita T, Epigenetic regulation of BMP7 in the regenerative response to ischemia. J Am Soc Nephrol. 2008; 19: 1311-1320.
35. Ruiz-Andres O, Ortiz A, Sanz AB, Histone lysine crotonylation during acute kidney injury in mice. Dis Model Mech. 2016; 9: 633-645.
36. Tan J, Yan Y, Zhao TC, Class Ⅰ HDAC activity is required for renal protection and regeneration after acute kidney injury. Am J Physiol Renal Physiol. 2014; 307: F303-F316.
37. Shi Y, Xu L, Tang J, Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury. Am J Physiol Renal Physiol. 2017; 312: F502-F515.
38. Tang J, Shi Y, Liu N, Blockade of histone deacetylase 6 protect against cisplatin-induced acute kidney injury. Clin Sci (Lond). 2018; 132: 339-359.
39. Brandenburger T, Salgado Somoza A, Lorenzen JM, Noncoding RNAs in acute kidney injury. Kidney Int. 2018; 94: 870-881.
40. Bellinger MA, Bean JS, Rader MA, Concordant changes of plasma and kidney microRNA in the early stage of acute kidney injury: time course in a mouse model of bilateral renal ischemia-reperfusion. PLoS One 2014; 9: e93297.
41. Saikumar J, Hoffman D, Kim TM, Expression, circulation, and excretion profile of microRNA-21, -155, and -18a following acute kidney injury. Toxicol Sci. 2012; 129: 256-267.
42. Wilflingseder J, Sunzenauer J, Toronyi E, Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles. PLoS One 2014; 9: e104164.
43. Lorenzen JM, Kaucsar T, Schauerte C, MicroRNA-24 antagonism prevents renal ischemia reperfusion injury. J Am Soc Nephrol. 2014; 25: 2717-2729.
44. Aguado-Fraile E, Ramos E, Conde E, A pilot study identifying a set of microRNAs as precise diagnostic biomarkers of acute kidney injury. PLoS One. 2015; 10: e0127175.
45. Chun N, Coca SG, He JC, A protective role for microRNA-688 in acute kidney injury. J Clin Invest. 2018; pli: 124923. Doi: 10.1172/JCI124923.
46. Lin J, Zhang X, Xue C, The long noncoding RNA landscape in hypoxic and inflammatory renal epithelial injury. Am J Physiol Renal Physiol. 2015; 309: F901-F913.
47. Köllong SC, Seeger H, Kistler A, Malat1 is dispensable for renal ischemia-reperfusion injury. Sci Rep. 2018; 8: 3438.
48. Yu TM, Palanisamy K, Sun KT, RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1α and LncRNA PRINS. Sci Rep. 2016; 6: 18424.
49. Darby IA, Hewitson TD, Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 2016; 365: 553-562.
50. Nangaku M, Hirakawa Y, Tanaka T, Epigenetic changes in the acute kidney injury-to-chronic kidney disease transition. Nephron 2017; 137: 256-259.
51. Zager RA, Johnson AC, Becker K, Acute unilateral ischemic renal injury induces progressive renal inflammation, lipid accumulation, histone modification, and ``end-stage`` kidney disease. Am J Physiol Renal Physiol. 2011; 301: F1334-F1345.
52. Hewitson TD, Holt SG, Smith ER, Epigenetic modifications to H3K9 in renal tubulointerstitial cells after unilateral ureteric obstruction and TGF-β1 stimulation. Front Pharmocol. 2017; 8: 307.
53. Zhou X, Zang X, Zhuang S, Enhancer of zeste homolog 2 inhibition attenuates renal fibrosis by maintaining smad7 and phosphatase and tensin homolog expression. J Am Soc Nephrol. 2016; 27: 2092-2108.
54. Gomez IG, Nakagawa N, Duffield JS, MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis. Am J Physiol Renal Physiol. 2016; 310: F931-F944.
55. Chung AC, Meng X, Lan HY, miR-192 mediates TGF-beta/smad3-driven renal fibrosis. J Am Soc Nephrol. 2010; 21: 1317-1325.
56. Denby L, Ramadas V, McClure J, miR-21 and miR-214 are consistently modulated during renal injury in rodet models. Am J Physiol Renal Physiol. 2011; 179: 661-672.
57. Meng XM, Nikolic-Paterson DJ, Lan HY, TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016; 12: 325-338.
58. Bai X, Tian J, Li X, MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of snail-induced epithelial-mesenchymal transition in diabetic nephropathy. Sci Rep. 2016; 6: 20475.
59. Bechtel W, McGoohan S, Zeisberg M, Methylation determine fibroblast activation and fibrogenesis in the kidney. Nat Med. 2010; 16: 544-550.
60. Tampe B, Steinle U, Zeisberg M, Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression. Kidney Int. 2017; 91: 157-176.
61. Tampe B, Tampe D, Zeisberg M, Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol. 2014; 25: 905-912.
62. Chang YT, Yang CC, Lin SL, DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys. J Clin Invest. 2016; 126: 721-731.
63. Tikoo K, Ali Y, Gupta C, 5-azacitidine prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein, pAKT and DNMT1 expression in chemical induced cancer rats. Toxicol Lett. 2009; 191: 158-166.
64. Hayashi K, Itoh H, Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease. Arch Immunol Ther Exp (Warsz). 2015; 63: 193-196.
65. Nanayakkara PW, Kiefte-de Jong JC, Smulders YM, Association between global leukocyte DNA methylation, renak function, carotid intima-media thickness and plasma homocysteine in patients with stage 2-4 chronic kidney disease. Nephrol Dial Transplant. 2008; 23: 2586-5892.
66. Smyth LJ, McKay GJ, McKnight AJ, DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease. Epigenetics 2014; 9: 366-376.
67. Larkin BP, Glastras SJ, Saad S, DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease. FASEB J. 2018; 32: 5215-5226.
68. Van beneden K, Geers C, Van Den Branden C, Valproric acid attenuates proteinuria and kidney injury. J Am Soc Nephrol. 2011; 22: 1863-1875.
69. Lefvre GM, Patel SR, Dressler GR, Altering a histone H3K4 methylation pathway in glomerular podocytes promotes a chronic kidney disease phenotype. PLoS Genet. 2010; 6: e1001142.
70. Yang L, Shah JV, Bonentre JV, Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010; 16: 535-543.
71. Shindo T, Doi S, Masaki T, TGF-β1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA. Sci Rep. 2018; 8: 14060.
72. Liu H, Fergusson MM, Castilho RM, Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317: 803-806.
73. Wolf I, Levanon-Cohen S, Bose S, Klotho: a tumor suppressor and an modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 2008; 27: 7094-7105.
74. Doi S, Zou Y, Togao O, Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem. 2011; 286: 8655-8665.
75. Hu MC, Kuro-o M, Moe OW, Secreted klotho and chronic kidney disease. Adv Exp Med Biol. 2012; 728: 126-157.
76. Sun CY, Chang SC, Wu MS, Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int. 2012; 81: 640-650.
77. Irifuku T, Doi S, Masaki T, Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression. Kidney Int. 2016; 89: 147-157.
78. Thakker RV, Genetics of parathyroid tumors. J Intern Med. 2016; 280: 574-583.
79. Chandrasekharappa SC, Guru SC, Marx SJ, Positional cloning of the gene for multiple endocrine neoplasia type 1. Science 1997; 276: 404-407.
80. Daniel FI, Cherubini K, Salum FG, The role of epigenetic transcription repression and DNA methyltransferase in cancer. Cancer 2011; 117: 677-687.
81. Svedlund J, Barazeghi E, Westin G, The histone methyltransferase EZH2, an oncogene common to benign and malignant parathyroid tumors. Endocr Relat Cancer. 2014; 21: 231-239.
82. Verdelli C, Corbetta S, Epigenetics alterations in parathyroid cancers. Int J Mol Sci. 2017; 18: E310.
83. Thran S, Bastepe M, GNAS spectrum of disorders. Curr Osteoporos Rep. 2015; 13: 146-158.
84. Elli FM, Bordogna P, Mantovani G, Mosaicism for GNAS methylation defects associated with psudohypoparathyroidism type 1B arose in early post-zygotic phases. Clin Epigenetics. 2018; 10: 16.
85. Hofman-Bang J, Gravesen E, Lewin E, Epigenetic methylation of parathyroid CaR and VDR promoters in experimental secondary hyperparathyroidism. Int J Nephrol. 2012; 2012: 123576.
86. Uchiyama T, Tatsumi N, Okabe M, Hypermethylation of the CaSR and VDR genes in the parathyroid glands in chronic kidney disease rats with high-phosphate diet. Hum Cell. 2016; 29: 155-161.


Most read articles by the same author(s)
