vtioВестник трансплантологии и искусственных органовRussian Journal of Transplantology and Artificial Organs1995-1191Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation10.15825/1995-1191-2015-1-147-156vtio-507Research ArticleОбзор литературыLiterature ReviewsПАТОГЕНЕТИЧЕСКИЕ МЕХАНИЗМЫ РАЗВИТИЯ ИШЕМИЧЕСКОГО И РЕПЕРФУЗИОННОГО ПОВРЕЖДЕНИЯ ПОЧКИ КАК ПЕРСПЕКТИВНЫЕ МИШЕНИ СПЕЦИФИЧЕСКОЙ ТЕРАПИИPATHOGENETIC MECHANISMS OF THE DEVELOPMENT OF ISCHEMIC AND REPERFUSION DAMAGE THE KIDNEYS AS A PROMISING TARGET SPECIFIC THERAPYВатазинА. В.VatazinA. V.НестеренкоИ. В.NesterenkoI. V.ЗулькарнаевА. Б.ZulkarnaevA. B.7059899@gmail.comШаховН. Л.ShakhovN. L.ГБУЗ МО «Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского», Москва, Российская ФедерацияРоссияGovernment Budget Health Institution of Moscow region «M.F. Vladimirsky Moscow Regional Research Clinical Institute», Moscow, Russian FederationRussian Federation201503042015171147156Copyright © Ватазин А.В., Нестеренко И.В., Зулькарнаев А.Б., Шахов Н.Л., 20152015Ватазин А.В., Нестеренко И.В., Зулькарнаев А.Б., Шахов Н.Л.Vatazin A.V., Nesterenko I.V., Zulkarnaev A.B., Shakhov N.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.transpl.ru/vtio/article/view/507

Ишемическое и реперфузионное повреждение является сложным многофакторным процессом, повреждающим почечный трансплантат. Знание и понимание патогенетических механизмов процессов повреждения позволяет применять различные биологические агенты для снижения данного повреждения. Однако применение большинства биологических агентов остается пока еще только в эксперименте. Цель данного обзора – показать участников патогенетических механизмов, главным образом воспалительных медиаторов (цитокинов, хемокинов), их взаимодействие и последствия их повреждающего воздействия на ткань почечного трансплантата. 

Ischemic and reperfusion injury is a complex, multifactorial process that damage kidney transplant. Knowledge and understanding of pathogenic mechanisms of damage processes allows the use of various biological agents to reduce this damage. However, the application of most of biological agents is still only in the experiment. The purpose of this survey show participants of pathogenetic mechanisms, mainly inflammatory mediators (cytokines, chemokines), their interactions, and the consequences of their damaging effects on the fabric kidney transplant. 

ишемическое и реперфузионное повреждениеТолл-подобные рецепторынуклеарный фактор – κВцитокиныхемокиныischemic and reperfusion injuryToll-like receptorsNF-κBcytokineschemokinesReferencesКаабак ММ. Послеоперационное лечение реперфузионного повреждения трансплантированной почки: новый взгляд на патогенез реперфузионной травмы: дис. М., 2003. Kaabak MM. Post-operative treatment of reperfusion damage of the transplanted kidney: a new approach to the pathogenesis reperfusion injury: dis. M., 2003. (in Rus).Каабак ММ. Послеоперационное лечение реперфузионного повреждения трансплантированной почки: новый взгляд на патогенез реперфузионной травмы: дис. М., 2003. Kaabak MM. Post-operative treatment of reperfusion damage of the transplanted kidney: a new approach to the pathogenesis reperfusion injury: dis. M., 2003. (in Rus).Patschan D, Patschan S, Muller GA. Inflammation and microvasculopathy in Renal Ischemia Reperfusion Injury. Hindawi Publishing Corporation Journal of Transplantation. 2012; Article ID 764154: 7.Patschan D, Patschan S, Muller GA. Inflammation and microvasculopathy in Renal Ischemia Reperfusion Injury. Hindawi Publishing Corporation Journal of Transplantation. 2012; Article ID 764154: 7.Boros P, Bromberg JS. New Cellular and Molecular Immune Pathways in Ischemia/Reperfusion Injury. American Journal of Transplantation. 2006; 6: 652–658.Boros P, Bromberg JS. New Cellular and Molecular Immune Pathways in Ischemia/Reperfusion Injury. American Journal of Transplantation. 2006; 6: 652–658.Bergler T1, Hoffmann U, Bergler E. Toll-like receptor 4 in experimental kidney transplantation: early mediator of endogenous danger signals. Nephron Exp Nephrol. 2012; 121 (3–4): e59–70.Bergler T1, Hoffmann U, Bergler E. Toll-like receptor 4 in experimental kidney transplantation: early mediator of endogenous danger signals. Nephron Exp Nephrol. 2012; 121 (3–4): e59–70.Kristin Moretha, Helena Freya, Mario Huboa. Biglycantriggered TLR-2and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury. Matrix Biology. 28 January 2014.Kristin Moretha, Helena Freya, Mario Huboa. Biglycantriggered TLR-2and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury. Matrix Biology. 28 January 2014.Kristin Moreth, Rebekka Brodbeck, Andrea Babelova, Liliana Schaefer. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J. Clin. Invest. 2010; 120 (12): 4251–4272.Kristin Moreth, Rebekka Brodbeck, Andrea Babelova, Liliana Schaefer. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J. Clin. Invest. 2010; 120 (12): 4251–4272.Babelova A et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009; 284 (36): 24035–24048.Babelova A et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009; 284 (36): 24035–24048.Jinyang Zeng-Brouwers, Liliana Schaefer. Role of extracellular matrix components in renal pathophysiology. J. Matrix Biology. 2013. Available from: http://www.pzf. de/allg/research/schaefer.phpJinyang Zeng-Brouwers, Liliana Schaefer. Role of extracellular matrix components in renal pathophysiology. J. Matrix Biology. 2013. Available from: http://www.pzf. de/allg/research/schaefer.phpPopovic ZV1, Wang S, Papatriantafyllou M, Kaya Z. The proteoglycan biglycan enhances antigen-specific T-cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis. J. Immunol. 2011 Dec 15; 187 (12): 6217–6226.Popovic ZV1, Wang S, Papatriantafyllou M, Kaya Z. The proteoglycan biglycan enhances antigen-specific T-cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis. J. Immunol. 2011 Dec 15; 187 (12): 6217–6226.Kolářová H, Ambrůzová B, Svihálková Šindlerová L, Klinke A, Kubala L. Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions. Mediators Inflamm. 2014; 2014: 694312.Kolářová H, Ambrůzová B, Svihálková Šindlerová L, Klinke A, Kubala L. Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions. Mediators Inflamm. 2014; 2014: 694312.Bharadwaj A, Bydoun M, Holloway R, Waisman D. Annexin A2 heterotetramer: structure and function. Int. J. Mol. Sci. 2013 Mar 19; 14 (3): 6259–6305.Bharadwaj A, Bydoun M, Holloway R, Waisman D. Annexin A2 heterotetramer: structure and function. Int. J. Mol. Sci. 2013 Mar 19; 14 (3): 6259–6305.Antonios H. Tzamaloukas, Deepak Malhotra, Bradley H. Rosen. Principles of Management of Severe Hyponatremia. J. Am. Heart Assoc. Feb 2013; 2 (1): e005199.Antonios H. Tzamaloukas, Deepak Malhotra, Bradley H. Rosen. Principles of Management of Severe Hyponatremia. J. Am. Heart Assoc. Feb 2013; 2 (1): e005199.Lawson C, Wolf S. ICAM-1 signaling in endothelial cells. Pharmacol Rep. 2009 Jan-Feb; 61 (1): 22–32.Lawson C, Wolf S. ICAM-1 signaling in endothelial cells. Pharmacol Rep. 2009 Jan-Feb; 61 (1): 22–32.Hye Ryoun Jang, Hamid Rabb. The innate immune response in ischemic acute kidney injury. Clin. Immunol. 2009 January; 130 (1): 41–50.Hye Ryoun Jang, Hamid Rabb. The innate immune response in ischemic acute kidney injury. Clin. Immunol. 2009 January; 130 (1): 41–50.de Vries DK1, Lindeman JH, Tsikas D, de Heer E, Roos A. Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft. Am. J. Transplant. 2009 Jul; 9 (7): 1574–1584.de Vries DK1, Lindeman JH, Tsikas D, de Heer E, Roos A. Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft. Am. J. Transplant. 2009 Jul; 9 (7): 1574–1584.Rider P., Carmi Y. IL-1α and IL-1β recruit different myeloid cells and promote different stages of sterile inflammation. J. Immunol. 2011 Nov 1; 187 (9): 4835–4843.Rider P., Carmi Y. IL-1α and IL-1β recruit different myeloid cells and promote different stages of sterile inflammation. J. Immunol. 2011 Nov 1; 187 (9): 4835–4843.Nimesh SA. Patel. Endogenous IL-6 Enhances the Renal Injury, Dysfunction and Inflammation Caused by Ischemia/Reperfusion. Journal of Pharmacology and Experimental Therapeutics. 2009; 312 (3): 1170–1178.Nimesh SA. Patel. Endogenous IL-6 Enhances the Renal Injury, Dysfunction and Inflammation Caused by Ischemia/Reperfusion. Journal of Pharmacology and Experimental Therapeutics. 2009; 312 (3): 1170–1178.Sikka Gautam, Miller Karen, Berkowitz Dan, Barouch Lili. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. J. Experimental Gerontology. 2013 Feb; 48 (2): 128–135.Sikka Gautam, Miller Karen, Berkowitz Dan, Barouch Lili. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. J. Experimental Gerontology. 2013 Feb; 48 (2): 128–135.Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. March 2010; 10 (3): 170–181.Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. March 2010; 10 (3): 170–181.Hammer M, Mages J. Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur. J. Immunol. March 2010; 35 (10): 2991–3001.Hammer M, Mages J. Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur. J. Immunol. March 2010; 35 (10): 2991–3001.Sik Lee, Sarah Huen, Hitoshi Nishio, Saori Nishio. Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair. J. Am. Soc. Nephrol. Feb 2011; 22 (2): 317–326.Sik Lee, Sarah Huen, Hitoshi Nishio, Saori Nishio. Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair. J. Am. Soc. Nephrol. Feb 2011; 22 (2): 317–326.Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu. Rev. Immunol. 2009; 27: 485–517.Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu. Rev. Immunol. 2009; 27: 485–517.Li L, Liping Huang, Amy L. Vergis, Hong Ye. IL-17 produced by neutrophils regulates IFN-γ–mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. The Journal of Clinical Investigation. January 2010; 120 (1).Li L, Liping Huang, Amy L. Vergis, Hong Ye. IL-17 produced by neutrophils regulates IFN-γ–mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. The Journal of Clinical Investigation. January 2010; 120 (1).Jeffrey A. Leslie, M.D., Kirstan K. Meldrum. The Role of Interleukin-18 in Renal Injury. Journal of Surgical Research. 2008; 145: 170–175.Jeffrey A. Leslie, M.D., Kirstan K. Meldrum. The Role of Interleukin-18 in Renal Injury. Journal of Surgical Research. 2008; 145: 170–175.Therwa Hamza, John B. Barnett, Bingyun Li. Interleukin 12 a Key Immunoregulatory Cytokine in Infection Applications. Int. J. Mol. Sci. 2010; 11 (3): 789–806.Therwa Hamza, John B. Barnett, Bingyun Li. Interleukin 12 a Key Immunoregulatory Cytokine in Infection Applications. Int. J. Mol. Sci. 2010; 11 (3): 789–806.Qi Peng, Ke Li, Lesley A. Smyth, Guolan Xing. C3a and C5a Promote Renal Ischemia-Reperfusion Injury. J. Am. Soc. Nephrol. Sep 2012; 23 (9): 1474–1485.Qi Peng, Ke Li, Lesley A. Smyth, Guolan Xing. C3a and C5a Promote Renal Ischemia-Reperfusion Injury. J. Am. Soc. Nephrol. Sep 2012; 23 (9): 1474–1485.Kaabak M1, Babenko N, Kuznetsov O. Eculizumab reverses the potentially fatal effects of kidney graft reperfusion injury. Pediatr Transplant. 2014 Mar; 18 (2): E44–47.Kaabak M1, Babenko N, Kuznetsov O. Eculizumab reverses the potentially fatal effects of kidney graft reperfusion injury. Pediatr Transplant. 2014 Mar; 18 (2): E44–47.Lo DJ, Weaver TA, Kleiner DE, Mannon RB. Chemokines and their receptors in human renal allotransplantation. Transplantation. 2011 Jan 15; 91 (1): 70–77.Lo DJ, Weaver TA, Kleiner DE, Mannon RB. Chemokines and their receptors in human renal allotransplantation. Transplantation. 2011 Jan 15; 91 (1): 70–77.Kolattukudy PE, Niu J. Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. Circ. Res. 2012 Jan 6; 110 (1): 174–189.Kolattukudy PE, Niu J. Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. Circ. Res. 2012 Jan 6; 110 (1): 174–189.Fiorina P, Ansari MJ, Jurewicz M. Role of CXC chemokine receptor 3 pathway in renal ischemic injury. J. Am. Soc. Nephrol. 2006; 17: 716–723.Fiorina P, Ansari MJ, Jurewicz M. Role of CXC chemokine receptor 3 pathway in renal ischemic injury. J. Am. Soc. Nephrol. 2006; 17: 716–723.Bertini R, Barcelos LS. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br. J. Pharmacol. Jan 2012; 165 (2): 436–454.Bertini R, Barcelos LS. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br. J. Pharmacol. Jan 2012; 165 (2): 436–454.Andrew Siedlecki, William Irish, Daniel C. Brennan Delayed Graft Function in the Kidney Transplant. Am. J. Transplant. Nov 2011; 11 (11): 2279–2296.Andrew Siedlecki, William Irish, Daniel C. Brennan Delayed Graft Function in the Kidney Transplant. Am. J. Transplant. Nov 2011; 11 (11): 2279–2296.Furuichi K, Wada T, Iwata Y. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J. Am. Soc. Nephrol. 2003; 14: 2503–2515.Furuichi K, Wada T, Iwata Y. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J. Am. Soc. Nephrol. 2003; 14: 2503–2515.Ingrid Stroo, Geurt Stokman, Gwen JD Teske. Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase. Int. Immunol. Jun 2010; 22 (6): 433–442.Ingrid Stroo, Geurt Stokman, Gwen JD Teske. Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase. Int. Immunol. Jun 2010; 22 (6): 433–442.Victor E Laubach, Brent A French, Mark D Okusa. Targeting of Adenosine Receptors in Ischemia-Reperfusion Injury. Expert Opin Ther. Targets. Jan 2011; 15 (1): 103–118.Victor E Laubach, Brent A French, Mark D Okusa. Targeting of Adenosine Receptors in Ischemia-Reperfusion Injury. Expert Opin Ther. Targets. Jan 2011; 15 (1): 103–118.Sanchez A, Tripathy D. RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons. Neuropeptides. 2009 Aug; 43 (4): 315–320.Sanchez A, Tripathy D. RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons. Neuropeptides. 2009 Aug; 43 (4): 315–320.Rogers NM, Stephenson MD. Amelioration of renal ischemia–reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells. Br. J. Pharmacol. May 2012; 166 (1): 194–209.Rogers NM, Stephenson MD. Amelioration of renal ischemia–reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells. Br. J. Pharmacol. May 2012; 166 (1): 194–209.Xu Wang, Caroline Watson, Joshua S. Sharp. Oligomeric Structure of the Chemokine CCL5/RANTES from NMR, MS, and SAXS Data. Structure. Aug 10, 2011; 19 (8): 1138–1148.Xu Wang, Caroline Watson, Joshua S. Sharp. Oligomeric Structure of the Chemokine CCL5/RANTES from NMR, MS, and SAXS Data. Structure. Aug 10, 2011; 19 (8): 1138–1148.Matheus Correa-Costa, Hátylas Azevedo. Transcriptome Analysis of Renal Ischemia/Reperfusion Injury and Its Modulation by Ischemic Pre-Conditioning or Hemin Treatment. PLoS One. 2012; 7 (11): e49569.Matheus Correa-Costa, Hátylas Azevedo. Transcriptome Analysis of Renal Ischemia/Reperfusion Injury and Its Modulation by Ischemic Pre-Conditioning or Hemin Treatment. PLoS One. 2012; 7 (11): e49569.Furuichi K, Gao JL, Murphy PM. Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury. Am. J. Pathol. 2006; 169: 372–387.Furuichi K, Gao JL, Murphy PM. Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury. Am. J. Pathol. 2006; 169: 372–387.Li Li, Liping Huang. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia–reperfusion injury. Kidney Int. Dec 2008; 74 (12): 1526–1537.Li Li, Liping Huang. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia–reperfusion injury. Kidney Int. Dec 2008; 74 (12): 1526–1537.Li Li MD, Macrophages PhD. Dendritic cells and Kidney Ischemia-Reperfusion Injury. Semin Nephrol. May 2010; 30 (3): 268–277.Li Li MD, Macrophages PhD. Dendritic cells and Kidney Ischemia-Reperfusion Injury. Semin Nephrol. May 2010; 30 (3): 268–277.Grosse GM, Tryc AB. The temporal dynamics of plasma fractalkine levels in ischemic stroke: association with clinical severity and outcome. J. Neuroinflammation. 2014 Apr 10; 11(1):74.Grosse GM, Tryc AB. The temporal dynamics of plasma fractalkine levels in ischemic stroke: association with clinical severity and outcome. J. Neuroinflammation. 2014 Apr 10; 11(1):74.Furuichi K, Kaneko S, Wada T. Chemokine/chemokine receptor-mediated inflammation regulates pathologic changes from acute kidney injury to chronic kidney disease. Clin. Exp. Nephrol. 2009 Feb; 13 (1): 9–14.Furuichi K, Kaneko S, Wada T. Chemokine/chemokine receptor-mediated inflammation regulates pathologic changes from acute kidney injury to chronic kidney disease. Clin. Exp. Nephrol. 2009 Feb; 13 (1): 9–14.Vatazin AV, Siniutin AA, Zul'karnaev AB. Plasmapheresis in controlling of the severity of ischemia-reperfusion damage of renal transplant. J. Clin. Nephrology. 2013: 4.Vatazin AV, Siniutin AA, Zul'karnaev AB. Plasmapheresis in controlling of the severity of ischemia-reperfusion damage of renal transplant. J. Clin. Nephrology. 2013: 4.Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J. Transplant. 2013 Dec 24; 3 (4): 68–77.Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J. Transplant. 2013 Dec 24; 3 (4): 68–77.Zhang L1, Zhu Z, Liu J. Protective effect of N-acetylcysteine (NAC) on renal ischemia/reperfusion injury through Nrf2 signaling pathway. J. Recept Signal Transduct Res. 2014 Apr 15.Zhang L1, Zhu Z, Liu J. Protective effect of N-acetylcysteine (NAC) on renal ischemia/reperfusion injury through Nrf2 signaling pathway. J. Recept Signal Transduct Res. 2014 Apr 15.Wang X1, Tao T, Ding R. Kidney Protection against Ischemia/Reperfusion Injury by Myofibrillogenesis Regulator-1. Am. J. Nephrol. 2014 Apr 2; 39 (4): 279–287.Wang X1, Tao T, Ding R. Kidney Protection against Ischemia/Reperfusion Injury by Myofibrillogenesis Regulator-1. Am. J. Nephrol. 2014 Apr 2; 39 (4): 279–287.Ruan Y, Wang L, Zhao Y. Carbon monoxide potently prevents ischemia-induced high-mobility group box 1 translocation and release and protects against lethal renal ischemia-reperfusion injury. Kidney Int. 2014 Apr 2. doi: 10.1038/ki.2014.80.Ruan Y, Wang L, Zhao Y. Carbon monoxide potently prevents ischemia-induced high-mobility group box 1 translocation and release and protects against lethal renal ischemia-reperfusion injury. Kidney Int. 2014 Apr 2. doi: 10.1038/ki.2014.80.

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