Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Abstract

Renal ischemia-reperfusion injury (IRI) is a feature of ischemic acute renal failure and it impacts both short- and long-term graft survival after kidney transplantation. Complement activation has been implicated in renal IRI, but its mechanism of action is uncertain and the determinants of complement activation during IRI remain poorly understood. We engineered mice deficient in two membrane complement regulatory proteins, CD55 and CD59, and used them to investigate the role of these endogenous complement inhibitors in renal IRI. CD55-deficient (CD55−/−), but not CD59-deficient (CD59−/−), mice exhibited increased renal IRI as indicated by significantly elevated blood urea nitrogen levels, histological scores, and neutrophil infiltration. Remarkably, although CD59 deficiency alone was inconsequential, CD55/CD59 double deficiency greatly exacerbated IRI. Severe IRI in CD55−/−CD59−/− mice was accompanied by endothelial deposition of C3 and the membrane attack complex (MAC) and medullary capillary thrombosis. Complement depletion in CD55−/−CD59−/− mice with cobra venom factor prevented these effects. Thus, CD55 and CD59 act synergistically to inhibit complement-mediated renal IRI, and abrogation of their function leads to MAC-induced microvascular injury and dysfunction that may exacerbate the initial ischemic assault. Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55−/−CD59−/− mouse provides a useful animal model in this regard.

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

“…Although the protective role of CD59 in hepatic IRI has not been defined previously, the protective role of CD59 in renal IRI 26 and in cerebral ischemia 48 has been elucidated by utilization of deficiency of the mCd59a, a primary murine. 27,49,50 These results, together with the fact that CD59 is universally expressed in almost of all cells in a variety of organs, indicate that CD59 may protect against the IRI in organs other than liver, kidney, and brain.…”

“…Additionally, C6 deficiency in rats protects against ischemia damage in rat orthotopic liver transplantation (OLT) recipients, which indicates the role of MAC in the pathogenesis of hepatic IRI. 25,26 Nonetheless, the protective role of CD59 and the pathogenic role of complement, including MAC, in the pathogenesis of IRI still require further investigation.…”

High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation

“…Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured by the creatinase-peroxidase method and the urease-ultraviolet method, respectively (SRL, Tokyo, Japan 12 Ten viewing fields randomly selected from the outer medulla and corticomedullary junction on each slide section were examined at × 200 magnification. The interstitial fibrotic area was stained blue with Masson's trichrome staining, and a color image analyzer (WinROOF, ver.…”

Ischemia Reperfusion Induces IFN Regulatory Factor 4 in Renal Dendritic Cells, which Suppresses Postischemic Inflammation and Prevents Acute Renal Failure

“…Body temperature was continuously measured with a rectal probe and maintained at 36˚C-37˚C throughout the procedure by placing the mice on a heating pad. After clamp removal, the kidney was inspected for restoration of blood flow as evidenced by returning to its original color before closing the wound with standard sutures (35). To maintain fluid balance, all mice were supplemented with 0.5 ml saline.…”