Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

Abstract

Renal ischemia-reperfusion contributes to reduced renal allograft survival. The peptide B␤ 15-42 , a breakdown product of fibrin, attenuates inflammation induced by ischemia-reperfusion in the heart by competitively blocking the binding of leukocytes to endothelial VE-cadherin, but whether it could improve outcomes in renal transplantation is unknown. Here, we tested the ability of B␤ to ameliorate the effects of renal ischemic injury during allogenic kidney transplantation in mice. In our renal transplantation model (C57BL/6 into BALB/c mice), treatment with B␤ 15-42 at the time of allograft reperfusion resulted in significantly improved survival of recipients during the 28-day follow-up (60% versus 10%). B␤ 15-42 treatment decreased leukocyte infiltration, expression of endothelial adhesion molecules, and proinflammatory cytokines. Treatment significantly attenuated allogenic T cell activation and reduced cellular rejection. Moreover, B␤ 15-42 significantly reduced tubular epithelial damage and apoptosis, which we reproduced in vitro. These data suggest that B␤ 15-42 may have therapeutic potential in transplant surgery by protecting grafts from ischemia-reperfusion injury.

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

“…26 The mice were clamped for 16 (bilateral clamping) or 27 minutes (unilateral clamping). Mice were euthanized at 2 hours, 3 days, or 30 days postsurgery.…”

Role of fibrinogen in acute ischemic kidney injury

“…Interestingly, there was an increased inflammatory infiltrate in fibrinogen Ϫ/Ϫ grafts in transplantation experiments, whereas all groups had equal amounts of intrarenal infiltrate in the I/R model. These data suggest that leukocyte tissue infiltration is not only dependent on the binding of circulating fibrinogen to endothelial cells (1,20,21,38) but also affected by the presence of fibrinogen within the tissue.…”

“…Alternatively, it might be a valid strategy to target specific domains of the molecule since many biological functions identified for fibrinogen depend on distinct nonoverlapping epitopes (6). Along these lines, we and others (21,32,38,42) have previously demonstrated that the fibrinogen breakdown product, B␤15-42, has beneficial effects in renal I/R injury. Other domains of fibrinogen might be equally important, and their deletion might aggravate or attenuate I/R injury and inflammation independently of fibrinogen's coagulant function.…”

“…Renal I/R injury was induced through unilateral and bilateral clamping of the renal pedicles as previously described (38). Male fibrinogen ϩ/ϩ , fibrinogen ϩ/Ϫ , and fibrinogen Ϫ/Ϫ were anesthetized with isoflurane.…”

“…Vascularized kidney transplantation from male fibrinogen ϩ/ϩ , fibrinogen ϩ/Ϫ , and fibrinogen Ϫ/Ϫ mice to female fibrinogen Ϫ/Ϫ mice was performed as previously described (38). Briefly, mice were anesthetized with isoflurane, and the donor kidney and ureter were harvested en bloc including the renal artery with a small aortic cuff and the renal vein with a small caval cuff.…”