nefrНефрологияNephrology (Saint-Petersburg)1561-62742541-9439Pavlov First Saint-Petersburg State Medical Universitynefr-104Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEWS AND LECTURESХроническая болезнь почек: механизмы развития и прогрессирования гипоксического гломерулосклероза и тубулоинтерстициального фиброзаChronic kidney disease: mechanisms of hypoxic glomerulosclerosis and tubulointerstitial fibrosis development and progressionКузьминО. Б.KuzminO. B.noemail@neicon.ruОренбургский государственный медицинский университетРоссияOrenburg State Medical UniversityRussian Federation201501072015194616Copyright © Кузьмин О.Б., 20152015Кузьмин О.Б.Kuzmin O.B.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephrolog.ru/jour/article/view/104

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.

The review summarized recent data on the causes of chronic tissue hypoxia that occurs in kidneys in CKD and the mechanisms of development and progression of hypoxic glomerulosclerosis and tubulointerstitial fibrosis. Causes of chronic renal hypoxia are associated with the failure of the oxygen delivery, consumption, and arteriovenous shunting in renal cortical layer. The leading role among them have hypoperfusion of postglomerular capillary network due to the sclerotic glomerular injury and postglomerular capillaries loss, and local oxidative/nitrozative stress development, which increases oxygen consumption by kidney tissue cells. Additional risk factors which contribute to chronic renal hypoxia are anemia and hypoxemia, which are included in the mechanism of nephropathy formation in CKD patients with severe CHF. Nuclear transcription factor HIF-1a is expressed in podocytes and epithelial cells of proximal tubules influenced by chronic tissue hypoxia. This factor initiates intracellular signal pathways leading to epithelial-mesenchymal transformation of these cells into profibrotic phenotype cells and accelerating the processes of glomeruli and tubulointerstitial tissue sclerotic injure of. Elucidation of the causes of chronic renal hypoxia and the mechanisms underlying the development and progression of hypoxic glomerulosclerosis and tubulointerstitial fibrosis will go to development new approaches to CKD renoprotective therapy.

хроническая болезнь почекпочечная тканевая гипоксиягломерулосклерозтубулоинтерстициальный фиброзchronic kidney diseaserenal tissue hypoxiaglomerulosclerosistubulointerstitial fibrosisReferencesNangaki M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17 (1): 17-25Nangaki M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17 (1): 17-25Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 2008; 74 (7): 867-872Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 2008; 74 (7): 867-872Leong 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-F1733Leong 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-F1733Evans RG, Ince C, Joles JA et al. Haemodynamic influences on kidney oxygenation: Clinical implications of integrative physiology. Clin Exp Pharmacol Physiol 2013; 40 (2): 106-122Evans RG, Ince C, Joles JA et al. Haemodynamic influences on kidney oxygenation: Clinical implications of integrative physiology. Clin Exp Pharmacol Physiol 2013; 40 (2): 106-122Evans 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): F1259-1270Evans 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): F1259-1270Evans 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): 247-254Evans 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): 247-254Kang DH, Kanellis J, Hogo C et al. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002; 13 (3): 806-816Kang DH, Kanellis J, Hogo C et al. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002; 13 (3): 806-816Kang 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): 1434-1447Kang 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): 1434-1447Kang 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): 1448-1457Kang 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): 1448-1457Bohle 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): 191-195Bohle 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): 191-195Zhu 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);1854-1859Zhu 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);1854-1859Matsumoto 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): 1574-1571Matsumoto 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): 1574-1571Manotham 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): 1277-1288Manotham 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): 1277-1288Zhang B, Chen N, Shi W et al. Peritubular capillary loss is ameliorated by ramipril or valsartan treatment. Microcirculation 2008; 15 (4): 337-348Zhang B, Chen N, Shi W et al. Peritubular capillary loss is ameliorated by ramipril or valsartan treatment. Microcirculation 2008; 15 (4): 337-348Li 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-F1119Li 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-F1119Norman 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): 39-46Norman 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): 39-46McClellan W, Aronoff SL, Bolton WK et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin 2004; 20 (9): 1501-1510McClellan W, Aronoff SL, Bolton WK et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin 2004; 20 (9): 1501-1510Go 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- 2723Go 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- 2723Evans 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-R940Evans 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-R940Brown GC. Nitric oxide and mitochondria. Front Biosci 2007; 12 (6): 1024-1033Brown GC. Nitric oxide and mitochondria. Front Biosci 2007; 12 (6): 1024-1033Palm 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-F386Palm 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-F386Lai 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-F74Lai 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-F74O’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): 637-641O’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): 637-641Yoshida H, Yashiro M, Ping Liang et al. Mesangiolytic glomerulopathy in severe congestive heart failure. Kidney Int 1998; 53 (4): 880-891Yoshida H, Yashiro M, Ping Liang et al. Mesangiolytic glomerulopathy in severe congestive heart failure. Kidney Int 1998; 53 (4): 880-891Кузьмин ОБ. Механизмы развития и прогрессирования нефропатии у больных сердечной недостаточностью с хроническим кардиоренальным синдромом. Нефрология 2011; 15 (2): 20-29Кузьмин ОБ. Механизмы развития и прогрессирования нефропатии у больных сердечной недостаточностью с хроническим кардиоренальным синдромом. Нефрология 2011; 15 (2): 20-29Nangaku M, Inagi R, Miyata T, Fujita T. Hypoxia and hypoxia-inducible factor in renal disease. Nephron Exp Nephrol 2008; 110 (1): e1-7Nangaku M, Inagi R, Miyata T, Fujita T. Hypoxia and hypoxia-inducible factor in renal disease. Nephron Exp Nephrol 2008; 110 (1): e1-7Maxwell PH. Hypoxia-inducible factor as a physiological regulator. Exp Physiol 2005; 90 (6): 791-797Maxwell PH. Hypoxia-inducible factor as a physiological regulator. Exp Physiol 2005; 90 (6): 791-797Weidermann A, Bernhart WM, Klanke B et al. HIF activation protects from acute kidney injury. J Am Soc Nephrol 2008; 19 (2): 486-494Weidermann A, Bernhart WM, Klanke B et al. HIF activation protects from acute kidney injury. J Am Soc Nephrol 2008; 19 (2): 486-494Song 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): 77-85Song 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): 77-85Ding 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): 1081-1087Ding 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): 1081-1087Shodel 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): 857-867Shodel 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): 857-867Li 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): 569-583Li 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): 569-583Higgins 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-F1232Higgins 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-F1232Higgins 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): 3810-3820Higgins 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): 3810-3820Basu 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-F905Basu 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-F905Han 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): 1454-1462Han 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): 1454-1462Subtirelu M, Gershin I, Teichman J, Tufro A. A novel model of chronic hypoxia-induced glomerulomegaly (Abstract). J Am Soc Nephrol 2005; 16: 668ASubtirelu M, Gershin I, Teichman J, Tufro A. A novel model of chronic hypoxia-induced glomerulomegaly (Abstract). J Am Soc Nephrol 2005; 16: 668ABrukamp 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-F1407Brukamp 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-F1407Steenhard 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): 84-96Steenhard 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): 84-96Neusser MA, Liendmeyer MT, Moll AG et al. Human nephrosclerosis triggers: hypoxia-related glomerulopathy. Am J Pathol 2010; 176 (2): 594-607Neusser MA, Liendmeyer MT, Moll AG et al. Human nephrosclerosis triggers: hypoxia-related glomerulopathy. Am J Pathol 2010; 176 (2): 594-607Veron D, Reidy KJ, Bertuccio C et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 2010; 77 (11): 989-999Veron D, Reidy KJ, Bertuccio C et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 2010; 77 (11): 989-999Sahai A, Mei C, Schrier RW, Tannen RL. Mechanism of chronic hypoxia-induced renal cell growth. Kidney Int 1999; 56 (4): 1277-1281Sahai A, Mei C, Schrier RW, Tannen RL. Mechanism of chronic hypoxia-induced renal cell growth. Kidney Int 1999; 56 (4): 1277-1281Sodhi 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): 691-700Sodhi 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): 691-700Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 2010; 21 (2): 21-222Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 2010; 21 (2): 21-222Burns 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.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.Orphanides C, Fine LG, Norman JT. Hypoxia stimulates proximal tubular cell matrix production via TGF-ß1-independent mechanism. Kidney Int 1997; 52 (3): 637-647Orphanides C, Fine LG, Norman JT. Hypoxia stimulates proximal tubular cell matrix production via TGF-ß1-independent mechanism. Kidney Int 1997; 52 (3): 637-647Manotham K, Tanaka T, Matsumoto M et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int 2004; 65 (3): 871-880Manotham K, Tanaka T, Matsumoto M et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int 2004; 65 (3): 871-880Higgins 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): 3810-3820Higgins 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): 3810-3820Швецов 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): 66-70Швецов 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): 66-70Sun 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): 1278-1287Sun 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): 1278-1287Burns WC, Thomas MC. The molecular mediators of type epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev Med 2010; 12: e17Burns WC, Thomas MC. The molecular mediators of type epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev Med 2010; 12: e17Du 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): 2650-2659Du 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): 2650-2659Chung AC, Yu X, Lan NY. MicroRNA and nephropathy: emerging concepts. Int J Nephrol Renovascular Dis 2013; 6 (1): 169-179Chung AC, Yu X, Lan NY. MicroRNA and nephropathy: emerging concepts. Int J Nephrol Renovascular Dis 2013; 6 (1): 169-179Du 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): e30771Du 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): e30771Галишон П, Гертиг А. Эпителиально-мезенхимальная трансформация как биомаркер почечного фиброза: готовы ли мы применить теоретические знания на практике. Нефрология 2013; 17 (4): 9-16Галишон П, Гертиг А. Эпителиально-мезенхимальная трансформация как биомаркер почечного фиброза: готовы ли мы применить теоретические знания на практике. Нефрология 2013; 17 (4): 9-16

The authors declare that there are no conflicts of interest present.