Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya3279510.26442/terarkh201890692-97Editorial articleПередовая статьяReview ArticleThe role of podocytes dysfunction in chronic glomerulonephritis progressionРоль подоцитарной дисфункции в прогрессировании хронического гломерулонефритаChebotarevaN VЧеботареваНаталья Викторовна

к.м.н., доц. каф. внутренних, профессиональных болезней и пульмонологии медико-профилактического факультета; тел. +7(905)543-42-50; e-mail: natashatcheb@mail.ru; ORCID 0000-0003-2128-8560

natasha_tcheb@mail.ruBobkovaI NБобковаИрина Николаевна

д.м.н., проф. каф. внутренних, профессиональных болезней и пульмонологии медико-профилактического факультета

LysenkoL VЛысенкоЛидия Владимировна

д.м.н., проф. каф. внутренних, профессиональных болезней и пульмонологии медико-профилактического факультета

I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of RussiФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)15062018906VOL 90, NO6 (2018)ТОМ 90, №6 (2018)929711042020Copyright ©; 2018, Consilium MedicumCopyright ©; 2018, ООО "Консилиум Медикум"2018Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/32795

In the review, the mechanisms of podocytes damage underlying the development of proteinuria and progression of glomerulosclerosis in chronic glomerulonephritis are discussed in detail. The results of experimental and clinical studies are presented. Under the different immune and non-immune factors the podocytes form a stereotyped response to damage consisting in the reorganization of the actin cytoskeleton, foot process effacement, the detachment of podocytes from the glomerular basement membrane, and the appearance of specific podocyte proteins and whole cells (podocyturia) in the urine. Massive podocyturia in a limited proliferative capacity of podocytes leads to reduce their total count in the glomerulus (podocytopenia) and the development of glomerulosclerosis. The authors describe the line of markers of the podocyte injury and invasive and non-invasive methods of their assessment. In addition, the relationship of podocyturia level with proteinuria and renal dysfunction are discussed, the prospects of assessment the podocyte proteins in urine for assessing of glomerular damage severity and glomerulosclerosis risk are examined.

В обзоре рассмотрены механизмы повреждения подоцитов, лежащие в основе развития протеинурии и прогрессирования гломерулосклероза при хроническом гломерулонефрите, представлены результаты экспериментальных и клинических исследований по данным вопросам. Описывается, как под действием различных иммунных и неиммунных факторов подоциты формируют стереотипный ответ на повреждение, заключающийся в перестройке актинового цитоскелета, сглаживании ножковых отростков, отщеплении подоцитов с гломерулярной базальной мембраны и появлении в моче специфических подоцитарных белков и/или целых клеток (подоцитурия). Массивная подоцитурия при ограниченной пролиферативной способности подоцитов способствует снижению их общей массы в клубочке (подоцитопении) и развитию гломерулосклероза. Авторами описан спектр маркеров подоцитарного повреждения, освещены методы их инвазивной и неинвазивной оценки, проанализирована взаимосвязь их уровня с выраженностью протеинурии и дисфункции почек, рассмотрены перспективы исследования подоцитарных белков в моче для оценки тяжести гломерулярного повреждения, риска развития гломерулосклероза.

podocyturianephrinuriapodocyte dysfunctionpodocytopeniachronic glomerulonephritisподоцитуриянефринурияподоцитарная дисфункцияподоцитопенияхронический гломерулонефритShankland S.J. The podocyte’sresponse to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006;69:2131-47. doi:10.1038/sj.ki. 5000410Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83:253-307. doi: 10.1152/physrev.00020. 2002Pollak M.R. Inherited Podocytopathies: FSGS and Nephrotic Syndrome from a Genetic Viewpoint. J Am Soc Nephrol. 2002;13:3016-23. doi: 10.1097/01.ASN.0000039569.34360.5EKoop K, Eikmans M, Baelde H.J, Kawachi H, de Heer E, Paul L.C, Bruijn J.A. Expression of podocyte - associated molecules in acquired human kidney diseases. J Am Soc Nephrol. 2003;14:2063-71. doi: 10.1097/01. ASN.0000078803.53165.C9Patrakka J, Tryggvason K. New insights into the role of podocytes in proteinuria. Nat Rev Nephrol. 2009;5:463-8. doi:10.1038/nrneph. 2009.108Kriz W, Shirato I, Nagata M, Le Hir M, Lemley K.V. The podocyte’s response to stress: The enigma of foot process effacement. Am J Physiol Renal Physiol. 2013;304:333-47. doi: 10.1152/ajprenal.00478.2012Neal C.R. Podocytes: What’s under yours? (Podocytes and foot processes and how they change in nephropathy). Front Endocrinol. 23 February 2015. Available from: https://doi.org/10.3389/fendo.2015.00009Huber T.B, Bensing T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005;14 (3):211-6.Trimarchi H. Podocyturia: what is in a name? J Transl Int Med. 2015;3(2):51-6. doi: 10.1515/jtim-2015-0003Barisoni L, Schnaper H.W, Kopp J.B. A Proposed Taxonomy for the Podocytopathies: A Reassessment of the Primary Nephrotic Diseases. Clin J Am Soc Nephrol. 2007;2:529-42. doi: 10.2215/CJN.04121206Greka A, Mundel P. Cell biology and pathology of podocytes. Ann Rev Physiol. 2012;74:299-323. doi: 10.1146/annurev-physiol-020911-153238Couser W.G. Basic and translational concepts of immune - mediated glomerular diseases. J Am Soc Nephrol. 2012;23:381-99. doi: 10.1681/ ASN.2011030304Jefferson J.A, Shankland S.J, Pichler R.H. Proteinuria in diabetic kidney disease: A mechanistic viewpoint. Kidney Int. 2008;74:22-36. doi: 10.1038/ki.2008.128George B, Verma R, Soofi A, Garg P, Zhang J, Park T.J, Giardino L, Ryzhova L, Johnstone D, Wong H, Nihalani D, Salant D, Hanks S, Curran T, Rastaldi M, Holzman L. Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest. 2012;122:674-92. doi: 10.1172/ JCI60070Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi M, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe A, Kreidberg J, Mundel P. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004;113:1390-7. doi: 10.1172/JCI20402Shirato I. Podocyte process effacement in vivo. Micros Res Tech. 2002;57:241-6. doi: 10.1002/jemt.10082Le Hir M, Keller C, Eschmann V, Hähnel B, Hosser H, Kriz W. Podocyte bridges between the tuft and Bowman’s capsule: an early event in experimental crescentic glomerulonephritis. J Am Soc Nephrol. 2001;12:2060-71.Nagata M. Podocyte injury and its consequences. Kidney Int. 2016 Jun; 89(6):1221-30. doi: 10.1016/j.kint.2016.01.012Neal C, Crook H, Bell E, Harper S, Bates D. Three - dimensional reconstruction of glomeruli by electron microscopy reveals a distinct restrictive urinary subpodocyte space. J Am Soc Nephrol. 2005;16:1223-35. doi: 10.1681/ASN.2004100822Liapis H, Romagnani P, Anders H.J. New insights into the pathology of podocyte loss: mitotic catastrophe. Am J Pathol. 2013;183:1364-74. doi: 10.1016/j.ajpath.2013.06.033Vogelmann S.U, Nelson W.J, Myers B.D, Lemley K.V. Urinary excretion of viable podocytes in health and renal disease. Am J Physiol Renal Physiol. 2003;285(1):40-8. doi: 10.1152/ajprenal.00404.2002Garovic V.D, Wagner S.J, Petrovic L.M, Gray C.E, Hall P, Sugimoto H, Kalluri R, Grande J.P. Glomerular expression of nephrin and synaptopodin but not podocin is decreased in kidney sections from women with preeclampsia. Nephrol Dial Transplant. 2007;22:1136-43. doi: 10.1093/ndt/gfl711Hara A, Wada T, Furuchi K, Sakai N, Kawachi H, Shimizu F, Shibuya M, Matsushima K, Yokoyama H, Egashira K, Kaneko S. Blokade of VEGF accelerates proteinuria via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int. 2006;69(11):1986-95. doi: 10.1038/sj.ki.5000439Liu Y. New insights into epithelial - mesenchymal transitition contribute in kidney fibrosis. J Am Soc Nephrol. 2010;21:212-22. doi: 10.1681/ASN.2008121226Kriz W, Lemley K. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol. 2015;26:258-69. doi: 10.1681/ASN.2014030278Hara M, Yanagihara T, Kihara I. Urinary podocytes in primary focal segmental glomerulosclerosis. Nephron. 2001;89:342-7. doi: 10.1159/ 000046097Hara M, Yanagihara T, Kihara I, Higashi K, Fujimoto K, Kajita T. Apical cell membranes are shed into urine from injured podocytes: A novel phenomenon of podocyte injury. J Am Soc Nephrol. 2005;16:408-16. doi: 10.1681/ASN.2004070564Hara M, Yanagihara T, Kihara I. Cumulative excretion of urinary podocytes reflects disease progression in IgA nephropathy and Schönlein-Henoch purpura nephritis. Clin J Am Soc Nephrol. 2007;2:231-8. doi: 10.2215/CJN.01470506Sato Y, Wharram B.L, Lee S.K, Wickman L, Goyal M, Venkatareddy M, et al. Urine podocyte mRNAs mark progression of renal disease. J Am Soc Nephrol. 2009;20:1041-52. doi: 10.1681/ASN.2007121328Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Sekizuka K, et al. Urinary podocytes for the assessment of disease activity in lupus nephritis. Am J Med Sci. 2000;320:112-6. doi: 10.1097/00000441-200008000-00009Mansur J.B, Sabino A.R, Nishida S.K, Kirsztajn G.M. Is there a role for urinary podocyte excretion assessment in lupus nephritis? Ren Fail. 2016;38(4):643-7. doi: 10.3109/0886022X.2016.1150099Xu L, Yang H-C, Hao C-M, Lin S-T, Gu Y, Ma J. Podocyte number predicts progression of proteinuria in IgA nephropathy. Modern Pathology. 2010;23:1241-50. doi: 10.1038/modpathol.2010.110Morioka Y, Koike H, Ikezumi Y, Ito Y, Oyanagi A, Gejyo F, Shimizu F, Kawachi H. Podocyte exacerbate mesangial proliferative glomerulonephritis. Kidney Int. 2001;60(6):2192-204. doi: 10.1046/j.1523-1755.2001.00047.xYu D, Petermann A, Kunter U, Rong S, Shankland S.J, Floege J. Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. J Am Soc Nephrol. 2005;16:1733-41. doi: 10.1681/ASN.2005020159Doublier S, Ruotsalainen V, Salvidio G, Lupia E, Biancone L, Conaldi P.G, Reponen P, Tryggvason K, Camussi G. Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephritic syndrome. Am J Pathol. 2001;158(5):1723-31. doi: 10.1016/S0002-9440(10)64128-4Yuan H, Takeuchi E, Taylor G.A, Mc Laughlin M, Brown D, Salant D.J. Nephrin dissociates from actin, and its expression is reduced in early experimental membranous nephropathy. J Am Soc Nephrol. 2002;13: 946-56.Luimula P, Aaltonen P, Ahola H, Palmen T, Holthofer H. Alternatively spliced nephrin in experimental glomerular disease of the rat. Pediatr Res. 2000;48:759-62. doi: 10.1203/00006450-200012000-00010Nakatsue T, Koike H, Han G.D, Suzuki K, Miyauchi N, Yuan H, Salant D.J, Gejyo F, Shimizu F, Kawachi H. Nephrin and podocin dissociate at the onset of proteinuria in experimental membranous nephropathy. Kidney Int. 2005; 67:2239-53. doi: 10.1111/j.1523-1755.2005.00328.xBenzing T. Signaling at the slit diaphragm. J Am Soc Nephrol. 2004;15:1382-91. doi: 10.1097/01.ASN.0000130167.30769.55Gadliardini E, Benigni A, Tomasoni S, Abbate M, Kalluri R, Remuzzi G. Targeted downregulation of extracellular nephrin in human IgA nephropathy. Am J Nephrol. 2003;23:277-86. doi: 10.1159/000072281Patrakka J, Ruotsalainen V, Ketola I, Holmberg C, Heikinheimo M, Tryggvason K, Jalanko H. Expression of nephrin in pediatric kidney diseases. J Am Soc Nephrol. 2001;12:289-96.Яркова Н.А. Нефрин - ранний маркер повреждения почек при сахарном диабете 2-го типа. Лабораторная диагностика. 2017;2(47):101-3. doi: 10.21145/2499-9954-2017-2-101-103Huh W, Kim D.J, Kim M-K, Kim Y.G, Oh H-Y, Ruotsalainen V, Tryggvason K. Expression of nephrin in acquired human glomerular disease. Nephrol Dial Transplant. 2002;17:478-84 doi: 10.1093/ndt/ 17.3.478Чеботарева Н.В., Бобкова И.Н., Козловская Л.В. Нефринурия как показатель структурно - функциональных нарушений гломерулярного фильтра у больных протеинурическими формами нефрита. Клиническая нефрология. 2010;(4):45-51.Чеботарева Н.В., Бобкова И.Н., Непринцева Н.В., Козловская Л.В., Малкандуева З.Т. Мочевые биомаркеры подоцитарного повреждения, значение для оценки течения и прогноза хронического гломерулонефрита. Терапевтический архив. 2015;(6):34-9. doi: 10.17116/terarkh 201587634-39Proletov I, Galkina O, Bogdanova E, Zubina I, Sipovskii V, Smirnov A. Clinical significance of podocyte injury markers evaluation in patients with primary glomerulopathies. Nephrol Dial Transplant. 2014;29: iii193.Kriz W, Greitz N, Lemley K.V. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 1998;54:687-97. doi: 10.1046/j. 1523-1755.1998.00044.xLuyckx V.A, Brenner B.M. The clinical importance of nephron mass. J Am Soc Nephrol. 2010;21:898-910. doi: 10.1681/ASN.2009121248Romagnani P, Lasagni L, Remuzzi G. Renal progenitors: An evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol. 2013;9:137-46. doi: 10.1038/nrneph.2012.290Angelotti M.L, Ronconi E, Ballerini L, Peired A, Mazzinghi B, Sagrinati C, et al. Characterization of renal progenitors committed toward the tubular lineage and their regenerative potential in renal tubular injury. Stem Cells. 2012;30:1714-25. doi: 10.1002/stem.1130Ronconi E, Sagrinati C, Angelotti M.L, Lazzeri E, Mazzinghi B, et al. Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol. 2009;20(2):322-32. doi: 10.1681/asn.2008070709Pavenstadt H. Roles of the podocyte in glomerular function. Am J Physiol. 2000;278:173-9. doi: 10.1152/ajprenal.2000.278.2.F173Schiffer M, Bitzer M, Roberts I.S. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001;108:807-16. doi: 10.1172/ JCI12367Kim Y.H, Goyal M, Kurnit D. Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int. 2001;60:957-68. doi: 10.1046/j.1523-1755.2001.060003957.xYamaguchi Y, Iwano M, Suzuki D. Epithelial - mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis. 2009;54:653-64. doi: 10.1053/j.ajkd. 2009.05.009Miyauchi M, Toyoda M, Kobayashi K. Hypertrophy and loss of podocytes in diabetic nephropathy. Intern Med. 2009;48:1615-20. doi: 10.2169/internalmedicine.48.2137Reidy K, Susztak K. Epithelial - mesenchymal transition and podocyte loss in diabetic kidney disease. Am J Kidney Dis. 2009;54:590-3. doi: 10.1053/j.ajkd.2009.07.003Petermann A.T, Pippin J, Durvasula R, Pichler R, Hiromuda K, Monkawa T, Couser W.G, Shankland S.J. Mechanical stretch induces podocyte hypertrophy in vitro. Kidney Int. 2005;67(1):157-66. doi: 10.1111/j.1523-1755.2005.00066.xPetermann A, Floege J. Podocyte damage resulting in podocyturia: a potential diagnostic marker to assess glomerular disease activity. Nephron Clin Pract. 2007;106(2):61-6. doi: 10.1159/000101799Colucci G, Floege J, Schena F.P. The urinary sediment beyond light microscopical examination. Nephrol Dial Transplant. 2006;21(6): 1482-5. doi: 10.1093/ndt/gfl223Li Y, Kang Y.S, Dai C, Kiss L.P, Wen X, Liu Y. Epithelial - to - mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. Am J Pathol. 2008; 172(2): 299-308. doi: 10.2353/ajpath.2008.070057Cheng S, Lovett D.H, Gelatinase A. (MMP-2) is necessary and sufficient for renal tubular cell epithelial - mesenchymal transformation. Am J Pathol. 2003;162:1937-49. doi: 10.1016/S0002-9440(10)64327-1Tan T.K, Zheng G, Hsu T.T, Wang Y, Lee V.W, Tian X, Wang Y, Cao Q, Wang Y, Harris D.C. Macrophage matrix metalloproteinase-9 mediates epithelial - mesenchymal transition in vitro in murine renal tubular cells. Am J Pathol. 2010;176:1256-70. doi: 10.2353/ajpath.2010.090188Cheng S, Pollock A.S, Mahimkar R, Olson J.L, Lovett D.H. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J. 2006;20:1898-900. doi: 10.1096/fj.06-5898fjeLemley K.V, Lafayette A, Safai G, Derby G, Blouch K, Squarer A, Myers B.D. Podocytopenia and disease severity in IgA nephropathy. Kidney Int. 2002;61:1475-85. doi: 10.1046/j.1523-1755.2002.00269.xPatari A, Forsblom C, Havana M, et al. Nephrinuria in diabetic nephropathy of type 1 diabetes. Diabetes. 2003;52:2969-74. doi: 10.2337/diabetes.52.12.2969Mallipattu S.K, He J.C. The podocyte as a direct target for treatment of glomerular disease? Am J Physiol Renal Physiol. 2016;311(1):F46-F51. doi: 10.1152/ajprenal.00184.2016Müller-Deile J, Schiffer M. Podocytes from the diagnostic and therapeutic point of view. Pflugers Arch. 2017;469(7-8):1007-15. doi: 10.1007/s00424-017-1993-z