Хроническая болезнь почек: механизмы развития и прогрессирования гипоксического гломерулосклероза и тубулоинтерстициального фиброза

В обзоре обобщаются современные данные о причинах хронической тканевой гипоксии, возникающей в почках при хронической болезни почек (ХБП), и механизмах развития и прогрессирования гипоксического гломерулосклероза и тубулоинтерстициального фиброза. Причины хронической почечной гипоксии связаны с нарушением доставки, потребления и артериовенозного шунтирования кислорода в корковом слое почки. Ведущее значение среди них имеют гипоперфузия постгломерулярной капиллярной сети, обусловленная склеротическим повреждением клубочков и потерей постгломерулярных капилляров, и развитие локального оксидативного/нитрозативного стресса, увеличивающего потребление кислорода клетками почечной ткани. Дополнительными факторами риска являются анемия и гипоксемия, которые включаются в механизм формирования нефропатии у больных с ХБП с выраженной ХСН. Под влиянием хронической тканевой гипоксии в подоцитах и эпителиальных клетках проксимальных канальцев экспрессируется ядерный транскрипционный фактор HIF-1 α, который запускает внутриклеточные сигнальные пути, ведущие к эпителиально-мезенхимальной трансформации этих клеток в клетки профибротического фенотипа и ускоряющие процессы склеротического повреждения клубочков и тубулоинтерстициальной ткани. Выяснение причин возникновения хронической почечной гипоксии и механизмов, лежащих в основе развития и прогрессирования гипоксического гломерулосклероза и тубулоинтерстициального фиброза, позволит подойти к разработке новых подходов к нефропротективной терапии ХБП.

хроническая болезнь почек, почечная тканевая гипоксия, гломерулосклероз, тубулоинтерстициальный фиброз

1. Nangaki M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17 (1): 17-25

2. Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 2008; 74 (7): 867-872

3. Leong C-L, Anderson WP, O’Connor PM, Evans RG. Evidence that renal arterial-venous oxygen shunting contribes to dynamic regulation of renal oxygenation. Am J Physiol Renal Physiol 2007; 292 (8): F1726-F1733

4. Evans RG, Ince C, Joles JA et al. Haemodynamic influences on kidney oxygenation: Clinical implications of integrative physiology. Clin Exp Pharmacol Physiol 2013; 40 (2): 106-122

5. Evans RG, Gardiner BS, Smith DW, O'Connor PM. Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis. Am J Physiol Renal Physiol 2008; 295 (5): F1259-1270

6. Evans RG, Goddard D, Eppel GA, O’Connor PM. Stabilty of tissue pO2 in the face of altered perfusion: a phenomenon specific to the renal cortex and independent of resting renal oxygen consumption. Clin Exp Pharmacol Physiol 2011; 38 (4): 247-254

7. Kang DH, Kanellis J, Hogo C et al. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002; 13 (3): 806-816

8. Kang D-H, Joly AH, Oh S-W et al. Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol 2001; 12 (7): 1434-1447

9. Kang D-H, Hughes J, Mazzalli M et al. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001; 12 (7): 1448-1457

10. Bohle A, Mackensen-Haen S, Wehrmann M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res 1996; 19 (3-4): 191-195

11. Zhu XY.Chade AR, Rodriquez-Porcel M et al. Cortical microvascular remodelling in the stenotic kidney: role of increased oxidative stress. Arterioscl Thromb Vasc Biol 2004; 24 (8);1854-1859

12. Matsumoto M, Tanaka T, Yamamoto T et al. Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J Am Soc Nephrol 2004; 15 (6): 1574-1571

13. Manotham K, Tanaka T, Matsumoto M et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc Nephrol 2004; 15 (5): 1277-1288

14. Zhang B, Chen N, Shi W et al. Peritubular capillary loss is ameliorated by ramipril or valsartan treatment. Microcirculation 2008; 15 (4): 337-348

15. Li N, Yi F-X, Spurrier JC et al. Production of superoxide through NADH oxidase in thick ascending limb of Henle’s loop in rat kidney. Am J Physiol Renal Physiol 2002; 282 (6): F1111-F1119

16. Norman ST, Stidwile R, Singer M et al. Angiotensin II blockade augments renal arterial microvascular pO2, indicating a novel potentially renoprotective action. Nephron Physiol 2003; 94 (2): 39-46

17. McClellan W, Aronoff SL, Bolton WK et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin 2004; 20 (9): 1501-1510

18. Go AS, Yang J, Ackerson LM et al. Hemoglobin level, chronic kidney disease and risk of death and hospitalization in adults with chronic heart failure: Anemia in Chronic Heart Failure: Outcomes and Recourse Utilization (ANCHOR) Study. Circulation 2006; 113 (23): 2713- 2723

19. Evans RG, Goddard D, Eppel GA, O’Connor PM. Factors that render the kidney susceptible to tissue hypoxia in hypoxemia. Am J Physiol Regul 2011; 300 (4): R931-R940

20. Brown GC. Nitric oxide and mitochondria. Front Biosci 2007; 12 (6): 1024-1033

21. Palm F, Nangaku M, Fasching A et al. Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia in the kidney via oxidative stress. Am J Physiol Renal Physiol 2010; 299 (2): F380-F386

22. Lai EY Luo Z, Onozato ML et al. Effect of antioxidant drug tempol on renal oxygenation in mice with reduced renal mass. Am J Physiol Renal Physiol 2012; 303 (1): F64-F74

23. O’Connor PM, Anderson WP, Kett MM, Evans RG. Renal preglomerular arterial-venous O2 shunting is a structural antioxidant defense mechanism of the renal cortex. Clin Exp Pharnacol Physiol 2006; 33 (3): 637-641

24. Yoshida H, Yashiro M, Ping Liang et al. Mesangiolytic glomerulopathy in severe congestive heart failure. Kidney Int 1998; 53 (4): 880-891

25. Кузьмин ОБ. Механизмы развития и прогрессирования нефропатии у больных сердечной недостаточностью с хроническим кардиоренальным синдромом. Нефрология 2011; 15 (2): 20-29

26. Nangaku M, Inagi R, Miyata T, Fujita T. Hypoxia and hypoxia-inducible factor in renal disease. Nephron Exp Nephrol 2008; 110 (1): e1-7

27. Maxwell PH. Hypoxia-inducible factor as a physiological regulator. Exp Physiol 2005; 90 (6): 791-797

28. Weidermann A, Bernhart WM, Klanke B et al. HIF activation protects from acute kidney injury. J Am Soc Nephrol 2008; 19 (2): 486-494

29. Song YR, You SJ, Lee YM et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney. Nephrol Dial Transplant 2010; 25 (1): 77-85

30. Ding M, Cui S, Li C et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 2006; 12 (9): 1081-1087

31. Shodel J, Bohr D, Klanke B et al. Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells. Kidney Int 2010; 78 (9): 857-867

32. Li X, Kimura H, Hirota K et al. Synergistic effect of hypoxia and TNF-alpha on production of PAI-1 in human proximal renal tubular cells. Kidney Int 2005; 88 (2): 569-583

33. Higgins DF, Biyu MP, Akai J et al. Hypoxic induction of CTGF is directly mediated by HIF-1. Am J Physiol Renal Physiol 2004; 287 (6): F1223-F1232

34. Higgins DF, Kimura K, Bernhardt WM et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007; 117 (12): 3810-3820

35. Basu RK, Hubchak S, Hayashida T et al. Interdependence of HIF-1 a and TGF-ß/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression. Am J Physiol Renal Physiol 2011; 300 (4): F898-F905

36. Han WO, Zhu Q, Hu J et al. Hypoxia-inducible factor prolyl-hydroxylase-2 mediates TGF-ß1-induced epithelial-mesenchymal transition renal tubular cells. Biochim Biophys Acta 2013; 1833 (6): 1454-1462

37. Subtirelu M, Gershin I, Teichman J, Tufro A. A novel model of chronic hypoxia-induced glomerulomegaly (Abstract). J Am Soc Nephrol 2005; 16: 668A

38. Brukamp K, Jin B, Moeller M, Haase VH. Hypoxia and podocyte-specific Vhlh deletion confer risk of glomerular disease. Am J Physiol Renal Physiol 2007; 293 (4): F1397-F1407

39. Steenhard BM, Isom K, Stroganova L et al. Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen IV, expression of neuroglobin and proteinuria. Am J Pathol 2010; 177 (1): 84-96

40. Neusser MA, Liendmeyer MT, Moll AG et al. Human nephrosclerosis triggers: hypoxia-related glomerulopathy. Am J Pathol 2010; 176 (2): 594-607

41. Veron D, Reidy KJ, Bertuccio C et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 2010; 77 (11): 989-999

42. Sahai A, Mei C, Schrier RW, Tannen RL. Mechanism of chronic hypoxia-induced renal cell growth. Kidney Int 1999; 56 (4): 1277-1281

43. Sodhi CP, Batlle D, Sahai A. Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK. Kidney Int 2000; 58 (2): 691-700

44. Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 2010; 21 (2): 21-222

45. Burns WC, Thomas MC. The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev Med 2010; 12: e17.

46. Orphanides C, Fine LG, Norman JT. Hypoxia stimulates proximal tubular cell matrix production via TGF-ß1-independent mechanism. Kidney Int 1997; 52 (3): 637-647

47. Manotham K, Tanaka T, Matsumoto M et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int 2004; 65 (3): 871-880

48. Higgins DF, Kimura K, Bernhardt WM et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007; 117 (2): 3810-3820

49. Швецов МЮ, Иванов АА, Попова ОП и др. Renal expression of hypoxia-induced factor-1, anemia and nephrosclerosis severity in chronic glomerulonephritis. Клин нефрол 2009; (2): 66-70

50. Sun S, Ning X, Zhang Y et al. Hypoxia-inducible factoralpha induces Twist expression in tubular epithelial cells subjected hypoxia, leading to epithelial-mesenchymal transition. Kidney Int 2009; 75 (12): 1278-1287

51. Burns WC, Thomas MC. The molecular mediators of type epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev Med 2010; 12: e17

52. Du R, Xia L, Liu L et al. Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal. Mol Biol Cell 2014; 25 (17): 2650-2659

53. Chung AC, Yu X, Lan NY. MicroRNA and nephropathy: emerging concepts. Int J Nephrol Renovascular Dis 2013; 6 (1): 169-179

54. Du R, Sun W, Xia Let al. Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells. PLos One 2012; 7 (2): e30771

55. Галишон П, Гертиг А. Эпителиально-мезенхимальная трансформация как биомаркер почечного фиброза: готовы ли мы применить теоретические знания на практике. Нефрология 2013; 17 (4): 9-16