Perioperative acute renal failure is a devastating complication with high mortality. Ischemia and reperfusion injury is a frequent cause of perioperative acute renal failure. We demonstrated during the first funding period that A1 adenosine receptor (AR) activation acutely protected against necrotic renal IR injury and reduced inflammation and apoptosis after IR injury in vivo via mechanisms involving Gi, ERK and PKC. This competitive renewal proposes to continue the investigation of the mechanisms of renal protection with A1 adenosine receptors (ARs) against ischemia reperfusion induced acute renal failure. Preliminary data generated suggest that the renal protection with A1AR activation appeared to be biphasic: acute renal protection waned 3-4 hrs after treatment but re-appeared about 16 hrs after initial treatment with A1 AR agonists. This phenomenon has never been described in the kidney prior to this application. Exciting preliminary data generated also suggest important roles for Akt and heat shock protein 27 (HSP27) phosphorylation and cytoskeletal filamentous actin (F-actin) stabilization to mediate acute renal protection following A1AR activation whereas induction of new HSP27 protein mediates the delayed renal protection following A1AR activation. These findings lead use to hypothesize that A1AR activation produces biphasic (early and delayed) renal protection via different cellular mechanisms: the early phase of renal protection involves HSP27 phosphorylation while the late phase of renal protection requires de novo HSP27 protein synthesis. To address this hypothesis, we have formulated the following 3 aims:
Aim #1 : To identify the signaling pathways by which A1 AR activation mediates early renal protection.
Aim #2 : To define the signal transduction pathways that mediate delayed renal protection following A1 AR activation.
Aim #3 : To determine the therapeutic benefit of modulating the acute and delayed signaling events initiated by A1 AR activation in vivo and in vitro. To test these aims, we will utilize both in vivo and in vitro models of IR injury. In vivo studies will involve well characterized renal IR injury in mice. For in vitro studies, we will use freshly isolated proximal tubules from A1WT and A1KO mice as well as human proximal tubule cells in culture. Our proposed research integrates whole animal, molecular, histblogical as well as biochemical techniques to aid in a better understanding of the cellular mechanisms of acute renal failure during and after IR injury. This, in turn, will contribute to improved therapeutic regimens for the protection of renal function in patients. ? ? ?
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