Роль эпигенетической модификации и возможности эпигенетической терапии при трансформации острого поражения почек в хроническую болезнь почек

Острое поражение почек (ОПП) является опасным для жизни состоянием. Вследствие значительной распространенности, повышенного риска осложнений, высокой смертности и высоких медицинских затрат ОПП стало глобальной проблемой для здравоохранения. Первоначально исследователи полагали, что почки обладают высокой способностью к регенерации и восстановлению, но исследования, проведенные за последние 20 лет, показали, что почки при ОПП во многих случаях становятся неспособными к восстановлению. Даже когда уровень креатинина в сыворотке возвращается к исходному уровню, структурные повреждения почек сохраняются в течение длительного времени, что приводит к развитию хронической болезни почек (ХБП). Механизм перехода ОПП в ХБП до конца не выяснен. Важную роль в этом процессе в качестве регуляторов экспрессии генов могут играть эпигенетические изменения, такие как модификация гистонов, метилирование ДНК и некодирующие РНК. Эпигенетические модификации индуцируются гипоксией, что способствует экспрессии генов, связанных с факторами воспаления, и секреции коллагена. В данном обзоре подробно рассматривается роль эпигенетических модификаций в прогрессировании ОПП и трансформации в ХБП, диагностическая ценность биомаркеров эпигенетических модификаций для прогнозирования хронического исхода ОПП, а также потенциальная роль воздействия на эпигенетические модификации с целью ингибирования перехода ОПП в ХБП и улучшения прогноза заболевания.

1. Büttner S., Stadler A., Mayer C., Patyna S., Betz C., Senft C. et al. Incidence, risk factors, and outcome of acute kidney injury in neurocritical care. J. Intensive Care Med. 2020;35(4):338–46.

2. Lewington A.J., Cerdá J., Mehta R.L. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 2013;84(3):457–67.

3. Mehta R.L., Cerdá J., Burdmann E.A., Tonelli M., García-García G., Jha V. et al. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet. 2015;385(9987):2616–43.

4. Kurzhagen J.T., Dellepiane S., Cantaluppi V., Rabb H. AKI: an increasingly recognized risk factor for CKD development and progression. J. Nephrol. 2020;33(6):1171–87.

5. Chawla L.S., Bellomo R., Bihorac A., Goldstein S.L., Siew E.D., Bagshaw S.M. et al. Acute kidney disease and renal recovery: consensus report of the acute disease quality initiative (ADQI) 16 workgroup. Nat. Rev. Nephrol. 2017;13(4):241–57.

6. Hannan M., Ansari S., Meza N., Anderson A.H., Srivastava A., Waikar S. et al. Risk factors for CKD progression: overview of fi ndings from the CRIC study. Clin. J. Am. Soc. Nephrol. 2021;16(4):648–59.

7. Jiang M., Bai M., Lei J., Xie Y., Xu S., Jia Z. et al. Mitochondrial dysfunction and the AKI to CKD transition. Am. J. Physiol. Renal Physiol. 2020;319(6):F1105–16.

8. Li C., Shen Y., Huang L., Liu C., Wang J. Senolytic therapy ameliorates renal fi brosis postacute kidney injury by alleviating renal senescence. Faseb J. 2021;35(1):e21229.

9. Wen Y., Parikh C.R. The aftermath of AKI: recurrent AKI, acute kidney disease, and CKD progression. J. Am. Soc. Nephrol. 2021;32(1):2–4.

10. Coca S.G., Singanamala S., Parikh C.R. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81(5):442–8.

11. Рей С.И., Бердников Г.А., Васина Н.В. Острое почечное по вреждение 2020: эпидемиология, критерии диагностики, по казания, сроки начала и модальность заместительной почечной терапии. Анестезиология и реаниматология. 2020;5:63–69.

12. Рей С.И., Васина Н.В., Марченкова Л.В., Котенко О.Н. Принципы организации заместительной почечной терапии в неотложной медицине Департамента здравоохранения города Москвы 2017. Медицинский алфавит. 2018;2(18–355):5–11.

13. Fiorentino M., Grandaliano G., Gesualdo L., Castellano G. Acute kidney injury to chronic kidney disease transition. Contrib. Nephrol. 2018;193:45–54.

14. Guzzi F., Cirillo L., Roperto R.M., Romagnani P., Lazzeri E. Molecular mechanisms of the acute kidney injury to chronic kidney disease transition: an updated view. Int. J. Mol. Sci. 2019;20(19):4941.

15. Ogbadu J., Singh G., Aggarwal D. Factors aff ecting the transition of acute kidney injury to chronic kidney disease: potential mechanisms and future perspectives. Eur. J. Pharmacol. 2019;865:172711.

16. Ullah M.M., Basile D.P. Role of renal hypoxia in the progression from acute kidney injury to chronic kidney disease. Semin. Nephrol. 2019;39(6):567–80.

17. do Valle Duraes F., Lafont A., Beibel M., Martin K., Darribat K., Cuttat R. et al. Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fi brosis. JCI Insight. 2020;5(3):e130651.

18. Tanaka S., Tanaka T., Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am. J. Physiol. Renal Physiol. 2014;307(11):F1187–95.

19. Tanaka T. Epigenetic changes mediating transition to chronic kidney disease: hypoxic memory. Acta Physiol. 2018;222(4):e13023.

20. Egger G., Liang G., Aparicio A., Jones P.A. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63.

21. Kelsey G., Stegle O., Reik W. Single-cell epigenomics: recording the past and predicting the future. Science. 2017;358(6359):69–75.

22. Feinberg A.P. The key role of epigenetics in human disease prevention and mitigation. N. Engl. J. Med. 2018;378(14):1323–34.

23. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat. Rev. Genet. 2018;19(2):81–92.

24. Guo C., Dong G., Liang X., Dong Z. Epigenetic regulation in AKI and kidney repair: mechanisms and therapeutic implications. Nat. Rev. Nephrol. 2019;15(4):220–39.

25. Shu S., Wang Y., Zheng M., Liu Z., Cai J., Tang C. et al. Hypoxia and hypoxia-inducible factors in kidney injury and repair. Cells. 2019;8(3):207.

26. Zhang Y., Sun Z., Jia J., Du T., Zhang N., Tang Y. et al. Overview of histone modifi cation. Adv. Exp. Med. Biol. 2021;1283:1–16.

27. Portela A., Esteller M. Epigenetic modifi cations and human disease. Nat. Biotechnol. 2010;28(10):1057–68.

28. Zhou X., Zang X., Ponnusamy M., Masucci M.V., Tolbert E., Gong R. et al. Enhancer of zeste homolog 2 inhibition attenuates renal fi brosis by maintaining Smad7 and phosphatase and tensin homolog expression. J. Am. Soc. Nephrol. 2016;27(7):2092–108.

29. Hewitson T.D., Holt S.G., Tan S.J., Wigg B., Samuel C.S., Smith E.R. Epigenetic modifi cations to H3K9 in renal tubulointerstitial cells after unilateral ureteric obstruction and TGF-β1 stimulation. Front. Pharmacol. 2017;8:307.

30. Naito M., Bomsztyk K., Zager R.A. Endotoxin mediates recruitment of RNA polymerase II to target genes in acute renal failure. J. Am. Soc. Nephrol. 2008;19(7):1321–30.

31. Naito M., Bomsztyk K., Zager R.A. Renal ischemia-induced cholesterol loading: transcription factor recruitment and chromatin remodeling along the HMG CoA reductase gene. Am. J. Pathol. 2009;174(1):54–62.

32. Zager R.A., Johnson A.C. Renal ischemia-reperfusion injury upregulates histone-modifying enzyme systems and alters histone expression at proinfl ammatory/profi brotic genes. Am. J. Physiol. Renal Physiol. 2009;296(5):F1032–41.

33. Johnson A.C., Ware L.B., Himmelfarb J., Zager R.A. HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury. Clin. J. Am. Soc. Nephrol. 2011;6(9):2108–13.

34. Sasaki K., Doi S., Nakashima A., Irifuku T., Yamada K., Kokoroishi K. et al. Inhibition of SET domain-containing lysine methyltransferase 7/9 ameliorates renal fi brosis. J. Am. Soc. Nephrol. 2016;27(1):203–15.

35. Fontecha-Barriuso M., Martin-Sanchez D., Ruiz-Andres O., Poveda J., Sanchez-Niño M.D., Valiño-Rivas L. et al. Targeting epigenetic DNA and histone modifi cations to treat kidney disease. Nephrol. Dial. Transplant. 2018;33(11):1875–86.

36. Liang H., Huang Q., Liao M.J., Xu F., Zhang T., He J. et al. EZH2 plays a crucial role in ischemia/reperfusion-induced acute kidney injury by regulating p38 signaling. Infl amm. Res. 2019;68(4):325–36.

37. Yu C., Zhuang S. Histone methyltransferases as therapeutic targets for kidney diseases. Front Pharmacol. 2019;10:1393.

38. Mimura I., Nangaku M., Kanki Y., Tsutsumi S., Inoue T., Kohro T. et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol. Cell Biol. 2012;32(15):3018–32.

39. Marumo T., Hishikawa K., Yoshikawa M., Fujita T. Epigenetic regulation of BMP7 in the regenerative response to ischemia. J. Am. Soc. Nephrol. 2008;19(7):1311–20.

40. Zager R.A., Johnson A.C., Becker K. Acute unilateral ischemic renal injury induces progressive renal infl ammation, lipid accumulation, histone modifi cation, and “end-stage” kidney disease. Am. J. Physiol. Renal Physiol. 2011;301(6):F1334–45.

41. Tang J., Zhuang S. Histone acetylation and DNA methylation in ische mia/reperfusion injury. Clin. Sci. 2019;133(4):597–609.

42. Hyndman K.A. Histone deacetylases in kidney physiology and acute kidney injury. Semin. Nephrol. 2020;40(2):138–47.

43. Hassan F.U., Rehman M.S., Khan M.S., Ali M.A., Javed A., Nawaz A. et al. Curcumin as an alternative epigenetic modulator: mechanism of action and potential eff ects. Front Genet. 2019;10:514.

44. Li H.F., Cheng C.F., Liao W.J., Lin H., Yang R.B. ATF3-mediated epigenetic regulation protects against acute kidney injury. J. Am. Soc. Nephrol. 2010;21(6):1003–13.

45. Levine M.H., Wang Z., Bhatti T.R., Wang Y., Aufhauser D.D., McNeal S. et al. Class-specifi c histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fi brosis formation. Am. J. Transplant. 2015;15(4):965–73.

46. Novitskaya T., McDermott L., Zhang K.X., Chiba T., Paueksakon P., Hukriede N.A. et al. A PTBA small molecule enhances recovery and reduces postinjury fi brosis after aristolochic acid-induced kidney injury. Am. J. Physiol. Renal Physiol. 2014;306(5):F496–504.

47. Skrypnyk N.I., Sanker S., Skvarca L.B., Novitskaya T., Woods C., Chiba T. et al. Delayed treatment with PTBA analogs reduces postinjury renal fi brosis after kidney injury. Am. J. Physiol. Renal Physiol. 2016;310(8):F705–16.

48. Kinugasa F., Noto T., Matsuoka H., Urano Y., Sudo Y., Takakura S. et al. Prevention of renal interstitial fi brosis via histone deacetylase inhibition in rats with unilateral ureteral obstruction. Transpl. Immunol. 2010;23(1–2):18–23.

49. Costalonga E.C., Silva F.M., Noronha I.L. Valproic acid prevents renal dysfunction and infl ammation in the ischemia-reperfusion injury model. Biomed. Res. Int. 2016;2016:5985903.

50. Zhang H., Zhang W., Jiao F., Li X., Zhang H., Wang L. et al. The nephroprotective eff ect of MS-275 on lipopolysaccharide (LPS)-induced acute kidney injury by inhibiting reactive oxygen species (ROS)-oxidative stress and endoplasmic reticulum stress. Med. Sci. Monit. 2018;24:2620–30.

51. Liu N., He S., Ma L., Ponnusamy M., Tang J., Tolbert E. et al. Blocking the class I histone deacetylase ameliorates renal fi brosis and inhibits renal fi broblast activation via modulating TGF-beta and EGFR signaling. PLoS One. 2013;8(1):e54001.

52. Xiong C., Guan Y., Zhou X., Liu L., Zhuang M.A., Zhang W. et al. Selective inhibition of class IIa histone deacetylases alleviates renal fi brosis. Faseb J. 2019;33(7):8249–62.

53. Zhang W., Guan Y., Bayliss G., Zhuang S. Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide- induced acute kidney injury. Am. J. Physiol. Renal Physiol. 2020;319(6):F1015–26.

54. Chen F., Gao Q., Wei A., Chen X., Shi Y., Wang H. et al. Histone deacetylase 3 aberration inhibits Klotho transcription and promotes renal fi brosis. Cell Death. Diff er. 2021;28(3):1001–12.

55. Chen X., Yu C., Hou X., Li J., Li T., Qiu A. et al. Histone deacetylase 6 inhibition mitigates renal fi brosis by suppressing TGF-β and EGFR signaling pathways in obstructive nephropathy. Am. J. Physiol. Renal Physiol. 2020;319(6):F1003–14.

56. Moore L.D., Le T., Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38.

57. Parry A., Rulands S., Reik W. Active turnover of DNA methylation during cell fate decisions. Nat. Rev. Genet. 2021;22(1):59–66.

58. Zhang C., Liang Y., Lei L., Zhu G., Chen X., Jin T. et al. Hypermethylations of RASAL1 and KLOTHO is associated with renal dysfunction in a Chinese population environmentally exposed to cadmium. Toxicol. Appl. Pharmacol. 2013;271(1):78–85.

59. Xu X., Tan X., Tampe B., Wilhelmi T., Hulshoff M.S., Saito S. et al. High-fi delity CRISPR/Cas9-based gene-specifi c hydroxymethylation rescues gene expression and attenuates renal fi brosis. Nat. Commun. 2018;9(1):3509.

60. Chen J., Zhang X., Zhang H., Liu T., Zhang H., Teng J. et al. Indoxyl sulfate enhance the hypermethylation of Klotho and promote the process of vascular calcifi cation in chronic kidney disease. Int. J. Biol. Sci. 2016;12(10):1236–46.

61. Bechtel W., McGoohan S., Zeisberg E.M., Müller G.A., Kalbacher H., Salant D.J. et al. Methylation determines fi broblast activation and fi brogenesis in the kidney. Nat. Med. 2010;16(5):544–50.

62. Tampe B., Steinle U., Tampe D., Carstens J.L., Korsten P., Zeisberg E.M. et al. Low-dose hydralazine prevents fi brosis in a murine model of acute kidney injury-to-chronic kidney disease progression. Kidney Int. 2017;91(1):157–76.

63. Tikoo K., Ali I.Y., Gupta J., Gupta C. 5-Azacytidine 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(2–3):158–66.

64. Chang Y.T., Yang C.C., Pan S.Y., Chou Y.H., Chang F.C., Lai C.F. et al. DNA methyltransferase inhibition restores erythropoietin production in fi brotic murine kidneys. J. Clin. Invest. 2016;126(2):721–31.

65. Yin S., Zhang Q., Yang J., Lin W., Li Y., Chen F. et al. TGFβ-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fi brosis. Biochim. Biophys. Acta Mol. Cell. Res. 2017;1864(7):1207–16.

66. Liu Z., Wang Y., Shu S., Cai J., Tang C., Dong Z. Non-coding RNAs in kidney injury and repair. Am. J. Physiol. Cell Physiol. 2019;317(2):C177–88.

67. Fan Y., Chen H., Huang Z., Zheng H., Zhou J. Emerging role of miRNAs in renal fi brosis. RNA Biol. 2020;17(1):1–12.

68. Bijkerk R., van Solingen C., de Boer H.C., van der Pol P., Khairoun M., de Bruin R.G. et al. Hematopoietic microRNA-126 protects against renal ischemia/reperfusion injury by promoting vascular integrity. J. Am. Soc. Nephrol. 2014;25(8):1710–22.

69. Hao J., Wei Q., Mei S., Li L., Su Y., Mei C. et al. Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6. Kidney Int. 2017;91(1):106–18.

70. Wei Q., Sun H., Song S., Liu Y., Liu P., Livingston MJ. et al. MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury. J. Clin. Invest. 2018;128(12):5448–64.

71. Chen W., Ruan Y., Zhao S., Ning J., Rao T., Yu W. et al. MicroRNA-205 inhibits the apoptosis of renal tubular epithelial cells via the PTEN/Akt pathway in renal ischemia-reperfusion injury. Am. J. Transl. Res. 2019;11(12):7364–75.

72. Lorenzen J.M., Kaucsar T., Schauerte C., Schmitt R., Rong S., Hübner A. et al. MicroRNA-24 antagonism prevents renal ischemia reperfusion injury. J. Am. Soc. Nephrol. 2014;25(12):2717–29. 73. Bhatt K., Wei Q., Pabla N., Dong G., Mi Q.S., Liang M. et al. MicroRNA-687 induced by hypoxia-inducible factor-1 targets phosphatase and tensin homolog in renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 2015;26(7):1588–96.

73. Yuan J., Benway CJ., Bagley J., Iacomini J. MicroRNA-494 promotes cyclosporine-induced nephrotoxicity and epithelial to mesenchymal transition by inhibiting PTEN. Am. J. Transplant. 2015;15(6):1682–91.

74. Guan H., Peng R., Mao L., Fang F., Xu B., Chen M. Injured tubular epithelial cells activate fi broblasts to promote kidney fi brosis through miR-150-containing exosomes. Exp. Cell Res. 2020;392(2):112007.

75. Huang S.J., Huang J., Yan Y.B., Qiu J., Tan R.Q., Liu Y. et al. The renoprotective eff ect of curcumin against cisplatin-induced acute kidney injury in mice: involvement of miR-181a/PTEN axis. Ren Fail. 2020;42(1):350–7.

76. Lv W., Fan F., Wang Y., Gonzalez-Fernandez E., Wang C., Yang L. et al. Therapeutic potential of microRNAs for the treatment of renal fi brosis and CKD. Physiol. Genomics. 2018;50(1):20–34.

77. Wang X., Xue N., Zhao S., Shi Y., Ding X., Fang Y. Upregulation of miR-382 contributes to renal fi brosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway. Cell Death Dis. 2020;11(8):620.