Механизмы повреждения почки

DOI: https://dx.doi.org/10.18565/urology.2019.2.103-107

А.И. Тарасенко, А.В. Алексеев, С.Ю. Максимова

1) ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» (Сеченовский Университет) Минздрава России, Москва, Россия; 2) ФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России, Уфа, Россия
В обзоре представлены результаты исследований последних лет, посвященные механизмам повреждения почки. Подробно освещены роль иммунной системы в инициации, развитии и исходе повреждения эпителия почечных канальцев; молекулярно-генетические и метаболические изменения, определяющие степень и последствия почечной травмы. Описаны механизмы восстановления почечной паренхимы и развития фиброза после прекращения воздействия повреждающих факторов.


1. Zuk A., Bonventre J.V. Acute Kidney Injury. Annu. Rev. Med. 2016;67:293–307.

2. Sancho-Martinez S.M., Lopez-Novoa J.M., Lopez-Hernandez F.J. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury Clin. Kidney J. 2015;8:548–559.

3. Kurts C., Panzer U., Anders H.J., Rees A.J. The immune system and kidney disease: Basic concepts and clinical implications. Nat. Rev. Immunol. 2013;13:738–753.

4. El-Achkar T.M., Hosein M., Dagher P.C. Pathways of renal injury in systemic gram-negative sepsis. Eur J Clin Invest. 2008;38:39–44.

5. Hauenstein A.V., Zhang L., Wu H. The hierarchical structural architecture of inflammasomes, supramolecular inflammatory machines. Curr. Opin. Struct. Biol. 2015;31:75–83.

6. Mudaliar H., Pollock C., Komala M.G., Chadban S., Wu H., Panchapakesan U.The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am. J. Physiol. Ren. Physiol. 2013;305:F143–F154.

7. Kalakeche R., et al. Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. J Am Soc Nephrol. 2011;22:1505–1516.

8. Murugan R., et al. Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy. Nephrol Dial Transplant. 2014;29:1854–1864.

9. Vander Heiden M.G., Cantley L.C., Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–1033.

10. Waltz P., Carchman E., Gomez H., Zuckerbraun B. Sepsis results in an altered renal metabolic and osmolyte profile. J Surg Res. 2016;202:8–12.

11. Tran M., et al. PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest. 2011;121:4003–4014.

12. Jeon S.M., Chandel N.S., Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2013;485:661–665.

13. Hall A.M., Rhodes G.J., Sandoval R.M., Corridon P.R., Molitoris B.A. In vivo multiphoton imaging of mitochondrial structure and function during acute kidney injury. Kidney Int. 2013;83:72–83.

14. Hoenig M.P., Zeidel M.L. Homeostasis, the milieu interieur, and the wisdom of the nephron. Clin. J. Am. Soc. Nephrol. 2014;9:1272–1281.

15. Zhan M., Brooks C., Liu F., Sun L., Dong Z. Mitochondrial dynamics: Regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int. 2013;83:568–581.

16. Hsiao H.W., et al. The decline of autophagy contributes to proximal tubular dysfunction during sepsis. Shock. 2012;37:289–296.

17. Jones D.P. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, 2008: C849–C868.

18. Gorin Y., Cavaglieri R.C., Khazim K., Lee D.Y., Bruno F., Thakur S., Fanti P., Szyndralewiez C., Barnes J.L., Block K. and Abboud H.E. Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes. Am J Physiol Renal Physiol 2015; 308: F1276–F1287.

19. Jha J.C., Gray S.P., Barit D., Okabe J., El-Osta A., Namikoshi T., Thallas-Bonke V., Wingler K., Szyndralewiez C., Heitz F., Touyz R.M., Cooper M.E., Schmidt HHHW, and Jandeleit-Dahm K.A. Genetic targeting or pharmacologic inhibition of NADPH oxidase Nox4 provides renoprotection in long-term diabetic nephropathy. J Am Soc Nephrol 25, 2014: 1237–1254.

20. Sies H. Role of metabolic H2O2 generation: Redox signalling and oxidantive stress. J Biol Chem, 2014; 289: 8735–8741.

21. Wang Y. Ding M., Chaudhari S., Ding Y., Yuan J., Stankowska D., He S., Krishnamorthy R., Cunningham J.T., and Ma R. Nuclear factor κB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells. J Biol Chem 2013; 288: 12852–12865.

22. New D.D., Block K., Bhandhari B., Gorin Y., and Abboud H.E. IGF-1 increases the expression of fibronectin by Nox4-dependent Akt phosphorylation in renal tubular epithelial cells. Am J Physiol Cell Physiol 2012; 302: C122–C130.

23. Takasu O., et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med. 2013;187:509–517.

24. Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta. 2011;1813:1269–1278.

25. Decuypere J.P., Ceulemans L.J., Agostinis P., Monbaliu D., Naesens M., Pirenne J., Jochmans I. Autophagy and the kidney: Implications for ischemia-reperfusion injury and therapy. Am. J. Kidney Dis. 2015; 66:699–709.

26. Zhan M., Brooks C., Liu F., Sun L., Dong Z. Mitochondrial dynamics: Regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int. 2013; 83:568–581.

27. Weinberg J.M. Mitochondrial biogenesis in kidney disease. J. Am. Soc. Nephrol. 2011; 22:431–446.

28. Lech M., Grobmayr R., Ryu M., Lorenz G., Hartter I., Mulay S.R., Susanti H.E.,Kobayashi K.S., Flavell R.A., Anders H.J. Macrophage phenotype controls long-term AKI outcomes – Kidney regeneration versus atrophy. J. Am. Soc. Nephrol. 2014; 25:292–304.

29. Basile D.P., et al. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol. 2016; 27:687–697.

30. Vega R.B., Huss J.M., Kelly D.P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000; 20:1868–1876.

31. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011; 7:684–696.

32. Grande M.T., Sánchez-Laorden B., López-Blau C., De Frutos C.A., Boutet A.,Arévalo M., et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015; 21:989–997.

33. Meng X.M., Tang P.M., Li J., Lan H.Y. TGF-β/Smad signaling in renal fibrosis. Front Physiol. 2015; 6:82.

34. López-Hernández F.J., López-Novoa J.M. Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res. 2012;347:141–154.

35. Tan R.J., Zhou D., Zhou L., Liu Y. Wnt/β-catenin signaling and kidney fibrosis. Kidney Int Suppl (2011) 2014; 4:84–90.

36. Maarouf O.H., Aravamudhan A., Rangarajan D., Kusaba T., Zhang V.,Welborn J., et al. Paracrine Wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-talk. J Am Soc Nephrol. 2016; 27:781–790.

37. DiRocco D.P., Kobayashi A., Taketo M.M., McMahon A.P, Humphreys B.D. Wnt4/β-catenin signaling in medullary kidney myofibroblasts. J Am Soc Nephrol. 2013; 24:1399–1412.

38. Zhou B., Liu Y., Kahn M., Ann DK, Han A., Wang H, et al. Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP) J Biol Chem. 2012; 287:7026–7038.

39. Kok H.M., Falke L.L., Goldschmeding R., Nguyen T.Q. Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease. Nat Rev Nephrol. 2014; 10:700–711.

40. Hao S., He W., Li Y., Ding H., Hou Y., Nie J., et al. Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol. 2011; 22:1642–1653.

41. Fabian S.L., Penchev R.R., St-Jacques B., Rao A.N., Sipila P., West K.A., et al. Hedgehog-Gli pathway activation during kidney fibrosis. Am J Pathol. 2012; 180:1441–1453.

42. Zhou L., Li Y., Hao S., Zhou D., Tan R.J., Nie J., et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling. J Am Soc Nephrol. 2015; 26:107–120.

43. Batenburg W.W., Danser A.H. (Pro)renin and its receptors: pathophysiological implications. Clin Sci (Lond) 2012; 123:121–133.

44. Zhou D., Tan R.J., Lin L., Zhou L., Liu Y. Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury. Kidney Int. 2013; 84:509–520.

45. Yang J., Liu Y. Delayed administration of hepatocyte growth factor reduces renal fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol. 2003; 284:F349–F357.

46. Kusaba T., Humphreys B.D. Controversies on the origin of proliferating epithelial cells after kidney injury. Pediatr. Nephrol. 2014; 29:673–679.

47. Sabin K., Kikyo N. Microvesicles as mediators of tissue regeneration. Transl. Res. 2014; 163:286–295.

48. Duffield J.S. Cellular and molecular mechanisms in kidney fibrosis. J. Clin. Investig. 2014;124:2299–2306.

Об авторах / Для корреспонденции

А в т о р д л я с в я з и: А. В. Алексеев – к.м.н., доцент кафедры урологии с курсом ИДПО БГМУ, Уфа, Россия; e-mail: alekseevdlt@mail.ru

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