Immune Cells in Ischemic Acute Kidney Injury

Author(s): Long Zheng, Wenjun Gao, Chao Hu, Cheng Yang*, Ruiming Rong*

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 8 , 2019

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Graphical Abstract:


Acute kidney injury (AKI) is a systemic disease characterized by acute loss of renal function and accumulation of end products of nitrogen metabolism. Ischemic AKI is the most common cause of AKI, and inflammatory responses are inevitablely involved in ischemic AKI. In the process of ischemic AKI, multiple factors are involved in activating and recruitment of immune cell to the injured kidney. These factors include DAMPs and HIFs released from the injured kidney, increased expression of adhesion molecules, the production of chemokines and cytokines, activation of complement system and TLRs as well as the permeability dysfunction of the renal vascular endothelium. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after ischemia reperfusion injury (IRI), with some of their subpopulations also participating in the repair process. Numerous studies of immune cells involved in the pathogenesis of AKI have enhanced the understanding of their possible mechanisms in AKI which might become the potential targets for the treatment of ischemic AKI. This review describes the function of the immune cells in the pathogenesis and repair of ischemic AKI and emphasizes the treatment of ischemic AKI potentially targeting them.

Keywords: Ischemic, acute kidney injury, immune cells, renal function, chemokines, cytokines.

Huen, S.C.; Cantley, L.G. Macrophages in renal injury and repair. Annu. Rev. Physiol., 2017, 79, 449-469.
Yang, Y.; Song, M.; Liu, Y.; Liu, H.; Sun, L.; Peng, Y.; Liu, F.; Venkatachalam, M.A.; Dong, Z. Renoprotective approaches and strategies in acute kidney injury. Pharmacol. Ther., 2016, 163, 58-73.
Thadhani, R.; Pascual, M.; Bonventre, J.V. Acute renal failure. N. Engl. J. Med., 1996, 334(22), 1448-1460.
Chertow, G.M.; Burdick, E.; Honour, M.; Bonventre, J.V.; Bates, D.W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol., 2005, 16(11), 3365-3370.
Coca, S.G.; Yusuf, B.; Shlipak, M.G.; Garg, A.X.; Parikh, C.R. Long-term risk of mortality and other adverse outcomes after acute kidney injury: A systematic review and meta-analysis. Am. J. Kidney Dis., 2009, 53(6), 961-973.
Jang, H.R.; Rabb, H. Immune cells in experimental acute kidney injury. Nat. Rev. Nephrol., 2015, 11(2), 88-101.
Bonavia, A.; Singbartl, K. A review of the role of immune cells in acute kidney injury. Pediatr. Nephrol., 2018, 33(10), 1629-1639.
Xu, H.; Chen, C.; Hu, L.; Hou, J. Gene-modified mesenchymal stem cell-based therapy in renal ischemia- reperfusion injury. Curr. Gene Ther., 2017, 17(6), 453-460.
Panah, F.; Ghorbanihaghjo, A.; Argani, H.; Asadi Zarmehri, M.; Nazari Soltan Ahmad, S. Ischemic acute kidney injury and klotho in renal transplantation. Clin. Biochem., 2018, 55, 3-8.
Rock, K.L.; Latz, E.; Ontiveros, F.; Kono, H. The sterile inflammatory response. Annu. Rev. Immunol., 2010, 28, 321-342.
Andringa, K.K.; Agarwal, A. Role of hypoxia-inducible factors in acute kidney injury. Nephron Clin. Pract., 2014, 127(1-4), 70-74.
Kelly, K.J.; Williams, W.W. Jr, Colvin, R.B.; Meehan, S.M.; Springer, T.A.; Gutierrez-Ramos, J.C.; Bonventre, J.V. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J. Clin. Invest., 1996, 97(4), 1056-1063.
Takada, M.; Nadeau, K.C.; Shaw, G.D.; Marquette, K.A.; Tilney, N.L. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J. Clin. Invest., 1997, 99(11), 2682-2690.
Araki, M.; Fahmy, N.; Zhou, L.; Kumon, H.; Krishnamurthi, V.; Goldfarb, D.; Modlin, C.; Flechner, S.; Novick, A.C.; Fairchild, R.L. Expression of IL-8 during reperfusion of renal allografts is dependent on ischemic time. Transplantation, 2006, 81(5), 783-788.
Fiorina, P.; Ansari, M.J.; Jurewicz, M.; Barry, M.; Ricchiuti, V.; Smith, R.N.; Shea, S.; Means, T.K.; Auchincloss, H. Jr, Luster, A.D.; Sayegh, M.H.; Abdi, R. Role of CXC chemokine receptor 3 pathway in renal ischemic injury. J. Am. Soc. Nephrol., 2006, 17(3), 716-723.
Thurman, J.M.; Ljubanovic, D.; Edelstein, C.L.; Gilkeson, G.S.; Holers, V.M. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J. Immunol., 2003, 170(3), 1517-1523.
Shigeoka, A.A.; Holscher, T.D.; King, A.J.; Hall, F.W.; Kiosses, W.B.; Tobias, P.S.; Mackman, N.; McKay, D.B. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J. Immunol., 2007, 178(10), 6252-6258.
Pulskens, W.P.; Teske, G.J.; Butter, L.M.; Roelofs, J.J.; van der Poll, T.; Florquin, S.; Leemans, J.C. Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury. PLoS One, 2008, 3(10), e3596.
Brodsky, S.V.; Yamamoto, T.; Tada, T.; Kim, B.; Chen, J.; Kajiya, F.; Goligorsky, M.S. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am. J. Physiol. Renal Physiol., 2002, 282(6), F1140-F1149.
Sutton, T.A.; Mang, H.E.; Campos, S.B.; Sandoval, R.M.; Yoder, M.C.; Molitoris, B.A. Injury of the renal microvascular endothelium alters barrier function after ischemia. Am. J. Physiol. Renal Physiol., 2003, 285(2), F191-F198.
Linas, S.L.; Shanley, P.F.; Whittenburg, D.; Berger, E.; Repine, J.E. Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys. Am. J. Physiol., 1988, 255(4 Pt 2), F728-F735.
Rouschop, K.M.; Roelofs, J.J.; Claessen, N.; da Costa Martins, P.; Zwaginga, J.J.; Pals, S.T.; Weening, J.J.; Florquin, S. Protection against renal ischemia reperfusion injury by CD44 disruption. J. Am. Soc. Nephrol., 2005, 16(7), 2034-2043.
Nakazawa, D.; Kumar, S.V.; Marschner, J.; Desai, J.; Holderied, A.; Rath, L.; Kraft, F.; Lei, Y.; Fukasawa, Y.; Moeckel, G.W.; Angelotti, M.L.; Liapis, H.; Anders, H.J. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J. Am. Soc. Nephrol., 2017, 28(6), 1753-1768.
Paller, M.S. Effect of neutrophil depletion on ischemic renal injury in the rat. J. Lab. Clin. Med., 1989, 113(3), 379-386.
Melnikov, V.Y.; Faubel, S.; Siegmund, B.; Lucia, M.S.; Ljubanovic, D.; Edelstein, C.L. Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice. J. Clin. Invest., 2002, 110(8), 1083-1091.
Li, H.; Han, S.J.; Kim, M.; Cho, A.; Choi, Y.; D’Agati, V.; Lee, H.T. Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI. Am. J. Physiol. Renal Physiol., 2018, 314(5), F809-F819.
Ferhat, M.; Robin, A.; Giraud, S.; Sena, S.; Goujon, J.M.; Touchard, G.; Hauet, T.; Girard, J.P.; Gombert, J.M.; Herbelin, A.; Thierry, A. Endogenous IL-33 contributes to kidney ischemia-reperfusion injury as an alarmin. J. Am. Soc. Nephrol., 2018, 29(4), 1272-1288.
Solez, K.; Morel-Maroger, L.; Sraer, J.D. The morphology of “acute tubular necrosis” in man: Analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine (Baltimore), 1979, 58(5), 362-376.
Huen, S.C.; Cantley, L.G. Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr. Nephrol., 2015, 30(2), 199-209.
Okabe, Y.; Medzhitov, R. Tissue biology perspective on macrophages. Nat. Immunol., 2016, 17(1), 9-17.
Lee, S.; Huen, S.; Nishio, H.; Nishio, S.; Lee, H.K.; Choi, B.S.; Ruhrberg, C.; Cantley, L.G. Distinct macrophage phenotypes contribute to kidney injury and repair. J. Am. Soc. Nephrol., 2011, 22(2), 317-326.
Jo, S.K.; Sung, S.A.; Cho, W.Y.; Go, K.J.; Kim, H.K. Macrophages contribute to the initiation of ischaemic acute renal failure in rats. Nephrol. Dial. Transplant., 2006, 21(5), 1231-1239.
Wang, S.; Zhang, C.; Li, J.; Niyazi, S.; Zheng, L.; Xu, M.; Rong, R.; Yang, C.; Zhu, T. Erythropoietin protects against rhabdomyolysis-induced acute kidney injury by modulating macrophage polarization. Cell Death Dis., 2017, 8(4), e2725.
Zhou, L.; Zhuo, H.; Ouyang, H.; Liu, Y.; Yuan, F.; Sun, L.; Liu, F.; Liu, H. Glycoprotein non-metastatic melanoma protein b (Gpnmb) is highly expressed in macrophages of acute injured kidney and promotes M2 macrophages polarization. Cell. Immunol., 2017, 316, 53-60.
Banchereau, J.; Briere, F.; Caux, C.; Davoust, J.; Lebecque, S.; Liu, Y.J.; Pulendran, B.; Palucka, K. Immunobiology of dendritic cells. Annu. Rev. Immunol., 2000, 18, 767-811.
Nace, G.; Evankovich, J.; Eid, R.; Tsung, A. Dendritic cells and damage-associated molecular patterns: Endogenous danger signals linking innate and adaptive immunity. J. Innate Immun., 2012, 4(1), 6-15.
Liu, Y.J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell, 2001, 106(3), 259-262.
Snelgrove, S.L.; Lo, C.; Hall, P.; Lo, C.Y.; Alikhan, M.A.; Coates, P.T.; Holdsworth, S.R.; Hickey, M.J.; Kitching, A.R. Activated renal dendritic cells cross present intrarenal antigens after ischemia-reperfusion injury. Transplantation, 2017, 101(5), 1013-1024.
Dong, X.; Swaminathan, S.; Bachman, L.A.; Croatt, A.J.; Nath, K.A.; Griffin, M.D. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int., 2007, 71(7), 619-628.
Schlichting, C.L.; Schareck, W.D.; Weis, M. Renal ischemia-reperfusion injury: New implications of dendritic cell-endothelial cell interactions. Transplant. Proc., 2006, 38(3), 670-673.
Zhou, T.; Sun, G.Z.; Zhang, M.J.; Chen, J.L.; Zhang, D.Q.; Hu, Q.S.; Chen, Y.Y.; Chen, N. Role of adhesion molecules and dendritic cells in rat hepatic/renal ischemia-reperfusion injury and anti-adhesive intervention with anti-P-selectin lectin-EGF domain monoclonal antibody. World J. Gastroenterol., 2005, 11(7), 1005-1010.
Ozaki, K.S.; Kimura, S.; Nalesnik, M.A.; Sico, R.M.; Zhang, M.; Ueki, S.; Ross, M.A.; Stolz, D.B.; Murase, N. The loss of renal dendritic cells and activation of host adaptive immunity are long-term effects of ischemia/reperfusion injury following syngeneic kidney transplantation. Kidney Int., 2012, 81(10), 1015-1025.
Zhang, T.; Song, N.; Fang, Y.; Teng, J.; Xu, X.; Hu, J.; Zhang, P.; Chen, R.; Lu, Z.; Yu, X.; Ding, X. Delayed ischemic preconditioning attenuated renal ischemia-reperfusion injury by inhibiting dendritic cell maturation. Cell. Physiol. Biochem., 2018, 46(5), 1807-1820.
Rabb, H.; Daniels, F.; O’Donnell, M.; Haq, M.; Saba, S.R.; Keane, W.; Tang, W.W. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am. J. Physiol. Renal Physiol., 2000, 279(3), F525-F531.
Burne, M.J.; Daniels, F.; El Ghandour, A.; Mauiyyedi, S.; Colvin, R.B.; O’Donnell, M.P.; Rabb, H. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Invest., 2001, 108(9), 1283-1290.
Faubel, S.; Ljubanovic, D.; Poole, B.; Dursun, B.; He, Z.; Cushing, S.; Somerset, H.; Gill, R.G.; Edelstein, C.L. Peripheral CD4 T-cell depletion is not sufficient to prevent ischemic acute renal failure. Transplantation, 2005, 80(5), 643-649.
Park, P.; Haas, M.; Cunningham, P.N.; Bao, L.; Alexander, J.J.; Quigg, R.J. Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes. Am. J. Physiol. Renal Physiol., 2002, 282(2), F352-F357.
Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Regulatory T cells and immune tolerance. Cell, 2008, 133(5), 775-787.
Kinsey, G.R.; Sharma, R.; Huang, L.; Li, L.; Vergis, A.L.; Ye, H.; Ju, S.T.; Okusa, M.D. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J. Am. Soc. Nephrol., 2009, 20(8), 1744-1753.
Lai, L.W.; Yong, K.C.; Lien, Y.H. Pharmacologic recruitment of regulatory T cells as a therapy for ischemic acute kidney injury. Kidney Int., 2012, 81(10), 983-992.
Bai, M.; Zhang, L.; Fu, B.; Bai, J.; Zhang, Y.; Cai, G.; Bai, X.; Feng, Z.; Sun, S.; Chen, X. IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway. Kidney Int., 2018, 93(4), 814-825.
Akcay, A.; Nguyen, Q.; Edelstein, C.L. Mediators of inflammation in acute kidney injury. Mediators Inflamm., 2009, 2009, 137072.
Zhang, C.; Zheng, L.; Li, L.; Wang, L.; Li, L.; Huang, S.; Gu, C.; Zhang, L.; Yang, C.; Zhu, T.; Rong, R. Rapamycin protects kidney against ischemia reperfusion injury through recruitment of NKT cells. J. Transl. Med., 2014, 12, 224.
Arrenberg, P.; Maricic, I.; Kumar, V. Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. Gastroenterology, 2011, 140(2), 646-655.
Hu, C.; Zhang, C.; Yang, C. The role of natural killer T cells in acute kidney injury: Angel or evil? Curr. Protein Pept. Sci., 2017, 18(12), 1200-1204.
Coquet, J.M.; Chakravarti, S.; Kyparissoudis, K.; McNab, F.W.; Pitt, L.A.; McKenzie, B.S.; Berzins, S.P.; Smyth, M.J.; Godfrey, D.I. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population. Proc. Natl. Acad. Sci. USA, 2008, 105(32), 11287-11292.
Halder, R.C.; Aguilera, C.; Maricic, I.; Kumar, V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J. Clin. Invest., 2007, 117(8), 2302-2312.
Li, L.; Huang, L.; Sung, S.S.; Lobo, P.I.; Brown, M.G.; Gregg, R.K.; Engelhard, V.H.; Okusa, M.D. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J. Immunol., 2007, 178(9), 5899-5911.
Yang, S.H.; Lee, J.P.; Jang, H.R.; Cha, R.H.; Han, S.S.; Jeon, U.S.; Kim, D.K.; Song, J.; Lee, D.S.; Kim, Y.S. Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J. Am. Soc. Nephrol., 2011, 22(7), 1305-1314.
Clatworthy, M.R. B-cell regulation and its application to transplantation. Transpl. Int., 2014, 27(2), 117-128.
Martin, F.; Kearney, J.F. B1 cells: Similarities and differences with other B cell subsets. Curr. Opin. Immunol., 2001, 13(2), 195-201.
Burne-Taney, M.J.; Ascon, D.B.; Daniels, F.; Racusen, L.; Baldwin, W.; Rabb, H. B cell deficiency confers protection from renal ischemia reperfusion injury. J. Immunol., 2003, 171(6), 3210-3215.
Jang, H.R.; Gandolfo, M.T.; Ko, G.J.; Satpute, S.R.; Racusen, L.; Rabb, H. B cells limit repair after ischemic acute kidney injury. J. Am. Soc. Nephrol., 2010, 21(4), 654-665.
Lee, H.T.; Kim, M.; Kim, M.; Kim, N.; Billings, F.T. 4th, D’Agati, V.D.; Emala, C.W. Sr. Isoflurane protects against renal ischemia and reperfusion injury and modulates leukocyte infiltration in mice. Am. J. Physiol. Renal Physiol., 2007, 293(3), F713-F722.
Jang, H.R.; Rabb, H. The innate immune response in ischemic acute kidney injury. Clin. Immunol., 2009, 130(1), 41-50.
Harmon, C.; Sanchez-Fueyo, A.; O’Farrelly, C.; Houlihan, D.D. Natural killer cells and liver transplantation: Orchestrators of rejection or tolerance? Am. J. Transplant., 2016, 16(3), 751-757.
Cooper, M.A.; Fehniger, T.A.; Caligiuri, M.A. The biology of human natural killer-cell subsets. Trends Immunol., 2001, 22(11), 633-640.
Zhang, Z.X.; Wang, S.; Huang, X.; Min, W.P.; Sun, H.; Liu, W.; Garcia, B.; Jevnikar, A.M. NK cells induce apoptosis in tubular epithelial cells and contribute to renal ischemia-reperfusion injury. J. Immunol., 2008, 181(11), 7489-7498.
Zhang, Z.X.; Shek, K.; Wang, S.; Huang, X.; Lau, A.; Yin, Z.; Sun, H.; Liu, W.; Garcia, B.; Rittling, S.; Jevnikar, A.M. Osteopontin expressed in tubular epithelial cells regulates NK cell-mediated kidney ischemia reperfusion injury. J. Immunol., 2010, 185(2), 967-973.
Cen, C.; Aziz, M.; Yang, W.L.; Nicastro, J.M.; Coppa, G.F.; Wang, P. Osteopontin blockade attenuates renal injury after ischemia reperfusion by inhibiting NK cell infiltration. Shock, 2017, 47(1), 52-60.

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Year: 2019
Page: [770 - 776]
Pages: 7
DOI: 10.2174/1389203720666190507102529
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