Complement Activation and Renal Ischemia/Reperfusion Injury

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): This R03 grant is associated with K08 DK064790, entitled "Complement and Ischemic Acute Renal Failure". During the first three years of that grant we have explored the mechanisms of complement activation after renal ischemia/reperfusion (I/R), the mechanisms of complement mediated injury to the kidney, and we have developed a novel inhibitor of the alternative complement pathway. While completing the experiments outlined in Specific Aim 1 of that grant, we found that proximal tubular epithelial cells (PTECs) respond to ischemia by synthesizing complement C3. The complement inhibitory protein expressed by PTECs is also ordinarily polarized to the basolateral surface of the cells, and this polarity is lost after ischemia. These changes favor activation of the alternative complement pathway on the basolateral surface of PTECs, and likely contribute to tubulointerstitial injury after I/R. Recent work has revealed that the mannose binding lectin (MBL) system may also cause complement activation through alternative pathway amplification, an idea we had not initially considered based upon the previously accepted models of complement activation. Expanding upon these findings, the experiments in the current proposal examine these novel mechanisms by which the alternative pathway becomes greatly amplified on the surface of injured PTECs. The overall hypothesis of this grant is that (1) MBL recognizes ischemic PTECs, initiating the activation of complement, and (2) absent expression of cell surface complement inhibitors is sufficient to permit uncontrolled amplification of the alternative complement pathway. These mechanisms of complement initiation and amplification, and the active synthesis of C3 by ischemic PTECs that we have previously demonstrated, explain why the alternative pathway is extensively activated in the kidney after I/R. The proposed studies will utilize a model of ischemic acute renal failure and an in vivo model of isolated alternative pathway mediated injury to the tubules. An in vitro model will also be used to explore the roles of specific proteins in complement activation on the surface of hypoxic PTECs. The proposed studies will enhance our understanding of the pathophysiology of ischemic acute renal failure, and will help reveal the molecular mechanisms by which local aseptic injury to PTECs is transformed into a systemic inflammatory response. The funds made available through this grant will assist the completion of these aims by providing for a full-time technician and by assisting with the animal costs associated with these studies. . Ischemic acute renal failure is a common disease and is associated with a mortality rate of greater than 50% in the intensive care unit setting. A number of complement inhibitors have become available, including a specific inhibitor of the alternative pathway that has been developed by our laboratory. The proposed studies should help delineate the benefits and limitations of complement inhibition as a therapy for ischemic acute renal failure, as well as expand our understanding of complement activation as a mediator of inflammation after renal tubular injury.