arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2014-20-6-492-500arthyper-152Research ArticleЛЕКЦИЯLECTUREРЕМОДЕЛИРОВАНИЯ ПОЧЕК И СЕРДЦА ПРИ ХРОНИЧЕСКОЙ БОЛЕЗНИ ПОЧЕК — МИШЕНЬ НЕФРОКАРДИОПРОТЕКЦИИMOLECULAR AND CELLULAR MECHANISMS AND MEDIATOR SYSTEM OF KIDNEY AND HEART REMODELING IN CHRONIC KIDNEY DISEASE — THE TARGET OF NEPHRO- AND CARDIOPROTECTIONБобковаИ. Н.BobkovaI. N.

Доктор медицинских наук, заведующая отделом нефрологии научно-исследовательского центра, профессор кафедры нефрологии и гемодиализа ГБОУ ВПО «Первый МГМУ им. И. М. Сеченова» Минздрава России.

Контактная информация: Бобкова Ирина Николаевна, ГБОУ ВПО Первый МГМУ им. И.М. Сеченова  Минздрава России, кафедра нефрологии и гемодиализа, ул. Трубецкая,  д. 8, стр. 2, Москва, Россия, 119991.  Тел.: +7(499)246–02–10. E-mail: irbo.mma@mail.ru2

Сorresponding author: Irina N. Bobkova, MD, PhD, Professor, First Moscow St at e Medi cal  Uni ver si t y named af t er I.M. Sechenov, Department of Nephrology and Hemodialysis, 8 Trubetskaya str., building 2, Moscow, Russia, 119991. Тел.: +7(499)246-02-10. E-mail: irbo.mma@mail.ru2

 

irbo.mma@mail.ru2КозловскаяЛ. В.KozlovskayaL. V.

Доктор медицинских наук, профессор кафедры внутренних, профессиональных заболеваний и пульмонологии ГБОУ ВПО «Первый МГМУ им. И. М. Сеченова» Минздрава России

MD, PhD, DSc, Professor, Department of Internal and Professional Diseases and Pulmonology

irbo.mma@mail.ru2НанчикееваМ. Л.NanchikeevaM. L.

Врач Областной клинической больницы г. Владимира

MD

irbo.mma@mail.ru2ЧеботарёваН. В.ChebotarevaN. V.

Кандидат медицинских наук, ведущий научный сотрудник отдела нефрологии научно-исследовательского центра ГБОУ ВПО «Первый МГМУ им. И. М. Сеченова» Минздрава России

MD, PhD, Leading Researcher, Research Department for Nephrology

irbo.mma@mail.ru2ЛиО. А.LiA. O.

Кандидат медицинских наук, старший научный сотрудник отдела нефрологии научно-исследовательского центра ГБОУ ВПО «Первый МГМУ им. И. М. Сеченова»

MD, PhD, Leading Researcher, Research Department for Nephrology

irbo.mma@mail.ru2Первый Московский государственный медицинский университет имени И. М. Сеченова, МоскваРоссияFirst Moscow State Medical University named after I. M. Sechenov, MoscowRussian FederationОбластная клиническая больница, ВладимирРоссияRegional Hospital, VladimirRussian Federation201406032015206492500Copyright © Бобкова И.Н., Козловская Л.В., Нанчикеева М.Л., Чеботарёва Н.В., Ли О.А., 20152015Бобкова И.Н., Козловская Л.В., Нанчикеева М.Л., Чеботарёва Н.В., Ли О.А.Bobkova I.N., Kozlovskaya L.V., Nanchikeeva M.L., Chebotareva N.V., Li A.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/152

The lecture reviews molecular and cellular mechanisms, which are cornerstone of structural and functional  remodeling and kidney and heart fibrosis formation in chronic kidney disease. The key ways linking kidney and heart remodeling, including myofibroblast formation by epithelial-mesenchymal and endotelial-mesenchymal transdifferentiation, extracellular matrix production, are presented. The role of angiotensin II, transforming growth factor Я1, plasminogen activator inhibitor type I, vascular endothelial growth factor, matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in mechanisms of fibro- and angiofibrogenesis are discussed. Further research of the molecular and cellular mechanisms of tissue fibrosis broadens our understanding about nephro- and cardioprotective effects of traditional approaches (angiotensin converting enzyme inhibitors or angiotensin II receptor blockers) and gives an opportunity for therapy targeting common mediators of fibro- and angiofibrogenesis in kidneys and heart.

ремоделирование почек и сердцаэпителиально-мезенхимальная трансдифференциацияэндотелиально-мезенхимальная еренциациямиофибробластыангиотензин IIмедиаторы фиброзанефрокардиопротекцияrenal and cardiac remodelingepithelial-mesenchymal transdifferentiationendothelial-mesenchymal transdifferentiationmyofibroblastsangiotensin IImediators of fibrosiscardionephroprotectionReferencesKalluri R, Neilson EG. Epithelial-mesenchymal transitition and its implication for fibrosis. J Clin Invest. 2003;112(12):1776–84.Kalluri R, Neilson EG. Epithelial-mesenchymal transitition and its implication for fibrosis. J Clin Invest. 2003;112(12):1776–1784.Yoshi mat su Y, Wat abe T. Rol e of TGF-β1 si gnal s i n endothelial-mesenchymal transitition in cardiac fibrosis. Intern J Inflam. 2011. 2011:724080–7.Yoshimatsu Y, Watabe T. Role of TGF-β1 signals in endothelial-mesenchymal transitition in cardiac fibrosis. International Journal of Inflammation. 2011;2011:724080–724087.Zeisberg M, Neilson EG. Biomarkers for epithelial-tomesenchymal transitition. J Clin Invest.2009;119(6):1429–37.Zeisberg M, Neilson EG. Biomarkers for epithelialto-mesenchymal transitition. J Clin Invest. 2009;119 (6):1429–1437.Leask A. Potential therapeutic targets for cardiac fibrosis: TGF-β, angiotensin, endothelin, CCN2 and PDGF? Partners of fibroblast activation. Circ Res. 2010;106(11):1675–80.Leask A. Potential therapeutic targets for cardiac fibrosis: TGF-β, angiotensin, endothelin, CCN2 and PDGF? Partners of fibroblast activation. Circulation Research. 2010;106(11):1675–1680.Li u Y. Epi t hel i al t o mesenchymal t ransi t i on i n renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 2004;15(1):1–12.Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 2004;15:1–12.Eddy AA, Fogo АВ. Plasminogen activator inhibitor-1in chronic kidney disease: evidence and mechanisms of action. J Am Soc Nephrol. 2006;17(11):2999–3012.Eddy AA, Fogo АВ. Plasminogen activator inhibitor-1in chronic kidney disease: evidence and mechanisms of action. J Am Soc Nephrol. 2006;17(11):2999–3012.. Ta k e d a N, Ma n a b e I . Ce l l u l a r i n t e r p l a y b e t we e n cardiomyocytes and nonmyocytes in cardiac remodeling. Intern J Inflam. 2011;2011:535241–53.Takeda N, Manabe I. Cellular interplay between cardiomyocytes and nonmyocytes in cardiac remodeling. International Journal of Inflammation. 2011;2011:535241–535253.Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Therap. 2009;123(2):255–78. 9. Zeisberg EM, Tarnavski O, Zeisberg M et al. Endothelialto-mesenchymal transitition contributes to cardiac fibrosis. Nature Medicine. 2007;13 (8):952–61.Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacology and Therapeutic. 2009;123:255–278.Li u Y. Ne w i ns i ght s i nt o e pi t he l i a l - me s e nc hyma l transitition contribute in kidney fibrosis. J Am Soc Nephrol. 2010;21:212–22.Zeisberg EM, Tarnavski O, Zeisberg M, DorfmanAL, McMullen JR, Gustafsson E et al. Endothelial-to-mesenchymal transitition contributes to cardiac fibrosis. Nature Medicine. 2007;13(8):952–961.Zeisberg EM, Kalluri R. Epithelial-to-mesenchymal transitition contributes in renal fibrosis. J Mol Med. 2004;82 (3):175–81.Liu Y. New insights into epithelial-mesenchymal transitition contribute in kidney fibrosis. J Am Soc Nephrol. 2010;21:212–222.Kriz W, Greitz N, Lemley KV. Progression of glomerular di seases: i s t he podocyt e t he cul pri t ? Ki dney Int . 1998; 54 (3):687–97.Zeisberg EM, Kalluri R. Epithelial-to-mesenchymal transitition contributesin renal fibrosis. Journal of molecular medicine. 2004;82(3):175–181.Lemley KV, Lafayette A, Safai G, Derby G, Blouch K, Squarer A, Myers BD. Podocytopenia and disease severity in IgA nephropathy. Kidney Int. 2002;61(4):1475–85.Kriz W, Greitz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 1998;54(3):687–697.Galichon P, Hertig A. Epithelial to mesenchymal transitition a biomarker in renal fibrosis: are we ready for bedside? Fibrogenesis Tissue Repair. 2011;4:11–17.Lemley KV, Lafayette A, Safai G, Derby G, Blouch K, Squarer A et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int. 2002;61(4):1475– 1485.Kriz W, Kaissling B, Le Hir M. Epithelial-mesenchymal transition in kidney fibrosis: fact or fantasy? J Clin Invest. 2011;121 (2):468–472.Galichon P, Hertig A. Epithelial to mesenchymal transitition a biomarker in renal fibrosis: are we ready for bedside? Fibrogenesis and Tissue repair. 2011;4:11–17.Мухин Н. А., Козловская Л. В., Бобкова И.Н, Плиева О. К., Чеботарёва Н. В., Щербак А. В. Индуцируемые протеинурией механизмы ремоделирования тубулоинтерстиция и возможности нефропротекции при гломерулонефрите. Вестник РАМН. 2005;1:3–8. [Mukhin NA, Kozlovskaya LV, Bobkova IN, Plieva OK, Chebotareva NV, Scherbak AV. Renal tubulointerstitium remodeling induced by proteinuria and nephroprotection in chronic glomerulonephritis. Vestnik RAMN. 2005;1:3–8. In Russian].Kriz W, Kaissling B, Le Hir M. Epithelial-mesenchymal transitition in kidney fibrosis: fact or fantasy? J Clin Invest. 2011;121:468–472.Козловская Л. В., Бобкова И. Н., Плиева О. К., Чеботарёва Н. В., Щербак А. В., Мухин Н. А. Значение исследования в моче молекулярных медиаторов иммунного воспаления и фиброза в почке при хроническом гломерулонефрите. Терапевт. арх. 2004;9:84–87. [Kozlovskaya LV, Bobkova IN, Plieva OK, Chebotareva NV, Scherbak AV, Muckhin NA. Significance of research in urine of molecular mediators of renal immune inflammation and fibrosis in chronic glomerulonephritis. Тerapevticheskiy arkhiv. 2004;9:84– 87. In Russian].Muckhin NA, Kozlovskaya LV, Bobkova IN, Plieva OK, Chebotareva NV, Scherbak AV. Renal tubulointerstitium remodeling induced by proteinuria and nephroprotection in chronic glomerulonephritis. Vestnik RAMN. 2005;1:3–8. In Russian.Нанчикеева М. Л. , Конечная Е. Я. , Буланов М. Н. , Гладкая А. А., Козловская Л. В. Возможности ранней диагностики поражения почек у больных гипертонической болезнью. Терапевт. арх. 2004;9:29–34. [Nanchikeeva ML, Konechnaya EY, Bulanov MN, Gladkaya AA. Possibilities of early diagnostics of kidney damage in patients with arterial hypertension. Тerapevticheskiy arkhiv. 2004;9:29–34. In Russian].Kozlovskaya LV, BobkovaIN, Plieva OK, Chebotareva NV, Scherbak AV, Muckhin NA. Significance of research in urine of molecular mediators of renal immune inflammation and fibrosisin chronic glomerulonephritis. Тerapevticheskiy arkhiv. 2004;9:84–87. In Russian.Нанчикеева М. Л., Козловская Л.В, Буланов М. Н., Конечная Е. Я., Гладкая А. А. Значение ультразвуковой диагностики в исследовании кардиоренальных взаимоотношений при гипертонической болезни. Ультразвуковая и функциональная диагностика. 2005;1:76–82. [Nanchikeeva ML, Kozlovskaya LV, Bulanov MN, Konechnaya EY, Gladkaya A. Significance of ultrasonic diagnostics in research of cardiorenal relationship in arterial hypertension. Ultrasonic and functional diagnostics. 2005;1:76–82. In Russian].Nanchikeeva ML, Konechnaya EY, Bulanov MN, Gladkaya AA. Possibilities of early diagnostics of kidney damage in patients with arterial hypertension. Тerapevticheskiy arkhiv. 2004;9:29–34. In Russian.Нанчикеева М. Л. Ранняя стадия поражения почек у больных гипертонической болезнью: клиническое значение, принципы профилактики. Автореферат диссертации на соискание ученой степени д. м.н. Москва; 2010. 46 c. [Nanchikeeva ML. Early stage of renal damage in patients with arterial hypertension: clinical significance, principles of prevention. Abstract of PhD thesis. Moscow. 2010:46 p. In Russian].Nanchikeeva ML, Kozlovskaya LV, Bulanov MN, Konechnaya EY, Gladkaya A. Significance of ultrasonic diagnostics in research of cardiorenal relationship in arterial hypertension. Ultrasonic and functional diagnostics. 2005;1:76–82. In Russian.Бобкова И. Н., Чеботарева Н. В., Козловская Л. В., Варшавский В. А., Голицына Е. П. Экскреция с мочой моноцитарного хемотаксического протеина-1 и трансформирующего фактора роста β1 как показатель прогрессирования хронического гломерулонефрита. Терапевт. арх. 2006;5:9–14. [Bobkova IN, Chebotareva NV, Kozlovskaya LV, Varshavskiy VA, Golitsina EP. Urinary excretion of MCP-1 and TGF-β1 as a marker of chronic glomerulonephritis progression. Тerapevticheskiy arkhiv. 2006;5:9–14. In Russian].Nanchikeeva ML. Early stage of renal damage in patients with arterial hypertension: clinical significance, principles of prevention. Abstract of P.H.D. thesis. Moscow. 2010:1–46. In Russian.Бобкова И. Н. Клеточно-молекулярные механизмы нефротоксического действия протеинурии: роль в прогрессировании хронического гломерулонефрита, пути воздействия. Автореферат диссертации на соискание ученой степени д. м.н. Москва; 2007. 48 c. [Bobkova IN. Cellular and molecular mechanisms of nephrotoxic action of proteinuria: role in chronic glomerulonephritis progression, way of influence. Abstract of PhD thesis. Moscow; 2007. 48 p. In Russian].Bobkova IN, Chebotareva NV, Kozlovskaya LV, Varshavskiy VA, Golitsina EP. Urinary excretion of MCP-1 and TGF-β1 as a marker of chronic glomerulonephritis progression. Тerapevticheskiy arkhiv. 2006;78(5):9–14. In Russian.Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 2004;65 (6):2003–2017.Bobkova IN. Cellular and molecular mechanisms of nephrotoxic action of proteinuria: role in chronic glomerulonephritis progression, way of influence. Abstract of P.H.D. thesis. Moscow. 2007:1–48. In Russian.Fogo AB, Kon V. The glomerulus — a view from the inside — the endothelial cell. Int J Biochem Cell Biol. 2010;42 (9):1388–1397.Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 2004;65(6):2003–2017.Fogo AB, Kon V. The glomerulus — a view from the inside the endothelial cell. Int J Biochem Cell Biol. 2010;42(9):1388–1397.Fogo AB, Kon V. The glomerulus — a view from the inside the endothelial cell. Int J Biochem Cell Biol. 2010;42(9):1388–1397.

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