CD59a Deficiency Exacerbates Ischemia-reperfusion Injury in Mice

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2004 Aug 28

PMID 15331407

Citations 14

Authors

Daniel Turnberg

Marina Botto

Margarita Lewis

Wuding Zhou

Steven H Sacks

B Paul Morgan

Mark J Walport

H Terence Cook

Affiliations

Soon will be listed here.

Abstract

The terminal complement components C5a and the membrane attack complex are involved in the pathogenesis of ischemia-reperfusion injury in many organs. CD59 is the major regulator of membrane attack complex formation. Mice deficient in the Cd59a gene (mCd59a-/-) were used to investigate the role of CD59 in renal ischemia-reperfusion injury. Unilateral ischemia-reperfusion injury was induced by clamping the left renal pedicle for 30 minutes under general anesthetic. Mice were studied at 72 hours and 2 weeks after ischemia-reperfusion injury. mCd59a-/- mice developed significantly greater tubular injury (P = 0.01), tubulointerstitial apoptosis (P = 0.02), and neutrophil influx (P = 0.04) than controls at 72 hours after ischemia-reperfusion. Two weeks after ischemia-reperfusion, mCd59a-/- mice exhibited more severe tubular damage predominantly in a corticomedullary distribution than controls (P = 0.02). Quantification of interstitial leukocytes revealed significantly greater numbers of infiltrating lymphocytes (but not macrophages) in mCd59a-/- mice than controls (P = 0.04) at 2 weeks. At both time points, significantly more C9 (as a marker of membrane attack complex) deposition occurred in a peritubular distribution in mCd59a-/- mice than controls. In conclusion, these results demonstrate that the lack of CD59a, by allowing unregulated membrane attack complex deposition, exacerbates both the tubular injury and the interstitial leukocyte infiltrate after ischemia-reperfusion injury in mice.

Citing Articles

The complement system in pediatric acute kidney injury.

Stenson E, Kendrick J, Dixon B, Thurman J Pediatr Nephrol. 2022; 38(5):1411-1425.

PMID: 36203104 PMC: 9540254. DOI: 10.1007/s00467-022-05755-3.

A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia-reperfusion injury.

Bongoni A, Vikstrom I, McRae J, Salvaris E, Fisicaro N, Pearse M Sci Rep. 2021; 11(1):21873.

PMID: 34750424 PMC: 8575974. DOI: 10.1038/s41598-021-01423-y.

Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy.

Zhu P, Bailey S, Lei B, Paulos C, Atkinson C, Tomlinson S Transplantation. 2017; 101(4):e75-e85.

PMID: 28045880 PMC: 5360489. DOI: 10.1097/TP.0000000000001625.

Epidermal growth factor attenuates tubular necrosis following mercuric chloride damage by regeneration of indigenous, not bone marrow-derived cells.

Yen T, Alison M, Goodlad R, Otto W, Jeffery R, Cook H J Cell Mol Med. 2014; 19(2):463-73.

PMID: 25389045 PMC: 4407604. DOI: 10.1111/jcmm.12478.

C3a and C5a promote renal ischemia-reperfusion injury.

Peng Q, Li K, Smyth L, Xing G, Wang N, Meader L J Am Soc Nephrol. 2012; 23(9):1474-85.

PMID: 22797180 PMC: 3431410. DOI: 10.1681/ASN.2011111072.

References

Cybulsky A, Takano T, Papillon J, McTavish A . Complement C5b-9 induces receptor tyrosine kinase transactivation in glomerular epithelial cells. Am J Pathol. 1999; 155(5):1701-11. PMC: 1866958. DOI: 10.1016/S0002-9440(10)65485-5. View

Meri S, Morgan B, Davies A, Daniels R, Olavesen M, Waldmann H . Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology. 1990; 71(1):1-9. PMC: 1384213. View

Saadi S, Holzknecht R, Patte C, Platt J . Endothelial cell activation by pore-forming structures: pivotal role for interleukin-1alpha. Circulation. 2000; 101(15):1867-73. DOI: 10.1161/01.cir.101.15.1867. View

Hughes J, Nangaku M, Alpers C, Shankland S, Couser W, Johnson R . C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis. Am J Physiol Renal Physiol. 2000; 278(5):F747-57. DOI: 10.1152/ajprenal.2000.278.5.F747. View

Zhou W, Farrar C, Abe K, Pratt J, Marsh J, Wang Y . Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest. 2000; 105(10):1363-71. PMC: 315463. DOI: 10.1172/JCI8621. View

Couser W, Pippin J, Shankland S . Complement (C5b-9) induces DNA synthesis in rat mesangial cells in vitro. Kidney Int. 2001; 59(3):905-12. DOI: 10.1046/j.1523-1755.2001.059003905.x. View

Park P, Haas M, Cunningham P, Alexander J, Bao L, Guthridge J . Inhibiting the complement system does not reduce injury in renal ischemia reperfusion. J Am Soc Nephrol. 2001; 12(7):1383-1390. DOI: 10.1681/ASN.V1271383. View

Holt D, Botto M, Bygrave A, Hanna S, Walport M, Morgan B . Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria. Blood. 2001; 98(2):442-9. DOI: 10.1182/blood.v98.2.442. View

Qin X, Miwa T, Aktas H, Gao M, Lee C, Qian Y . Genomic structure, functional comparison, and tissue distribution of mouse Cd59a and Cd59b. Mamm Genome. 2001; 12(8):582-9. DOI: 10.1007/s00335-001-2060-8. View

10.

Dobrina A, Pausa M, Fischetti F, Bulla R, Vecile E, Ferrero E . Cytolytically inactive terminal complement complex causes transendothelial migration of polymorphonuclear leukocytes in vitro and in vivo. Blood. 2002; 99(1):185-92. DOI: 10.1182/blood.v99.1.185. View

11.

Nauta A, Daha M, Tijsma O, van de Water B, Tedesco F, Roos A . The membrane attack complex of complement induces caspase activation and apoptosis. Eur J Immunol. 2002; 32(3):783-92. DOI: 10.1002/1521-4141(200203)32:3<783::AID-IMMU783>3.0.CO;2-Q. View

12.

Zhao H, Montalto M, Pfeiffer K, Hao L, Stahl G . Murine model of gastrointestinal ischemia associated with complement-dependent injury. J Appl Physiol (1985). 2002; 93(1):338-45. DOI: 10.1152/japplphysiol.00159.2002. View

13.

Arumugam T, Shiels I, Strachan A, Abbenante G, Fairlie D, Taylor S . A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats. Kidney Int. 2002; 63(1):134-42. DOI: 10.1046/j.1523-1755.2003.00737.x. View

14.

Thurman J, Ljubanovic D, Edelstein C, Gilkeson G, Holers V . Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol. 2003; 170(3):1517-23. DOI: 10.4049/jimmunol.170.3.1517. View

15.

Qin X, Krumrei N, Grubissich L, Dobarro M, Aktas H, Perez G . Deficiency of the mouse complement regulatory protein mCd59b results in spontaneous hemolytic anemia with platelet activation and progressive male infertility. Immunity. 2003; 18(2):217-27. DOI: 10.1016/s1074-7613(03)00022-0. View

16.

de Vries B, Kohl J, Leclercq W, Wolfs T, van Bijnen A, Heeringa P . Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J Immunol. 2003; 170(7):3883-9. DOI: 10.4049/jimmunol.170.7.3883. View

17.

Harris C, Hanna S, Mizuno M, Holt D, Marchbank K, Morgan B . Characterization of the mouse analogues of CD59 using novel monoclonal antibodies: tissue distribution and functional comparison. Immunology. 2003; 109(1):117-26. PMC: 1782952. DOI: 10.1046/j.1365-2567.2003.01628.x. View

18.

Turnberg D, Botto M, Warren J, Morgan B, Walport M, Cook H . CD59a deficiency exacerbates accelerated nephrotoxic nephritis in mice. J Am Soc Nephrol. 2003; 14(9):2271-9. DOI: 10.1097/01.asn.0000083901.47783.2e. View

19.

Yamada K, Miwa T, Liu J, Nangaku M, Song W . Critical protection from renal ischemia reperfusion injury by CD55 and CD59. J Immunol. 2004; 172(6):3869-75. DOI: 10.4049/jimmunol.172.6.3869. View

20.

Hill J, Ward P . The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med. 1971; 133(4):885-900. PMC: 2138969. DOI: 10.1084/jem.133.4.885. View