PROTEIN KINASE C IN ISCHEMIC RENAL INJURY AND REPAIR

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Protein kinase C (PKC) isozymes comprise a family of cellular kinases that regulate cell growth and differentiation via phosphorylation of target proteins. PKC plays a role in the cellular response to ischemia in various tissues including kidney. We have shown that the expression of several PKC isozymes and the receptor for activated C-kinase(RACK1) are enhanced following ischemic renal injury. The studies outlined in this proposal are designed to delineate the role of individual PKC isozymes in the tubular regeneration following experimental acute ischemic renal injury using in vitro and in vivo models. The first aim of the proposed research is to localize individual PKC isozymes to particular cells that are undergoing regeneration or death. PKC assays will be performed to determine which of the individual isozymes are activated or down-regulated following ischemic injury. The second aim of the proposal is to determine if PKC plays a role in maintaining cellular viability and promoting regeneration of LLCPK1 cells following oxidant injury. LLCPK1 cells will be subjected to oxidant injury in presence of activators and inhibitors of PKC and their effects on cell viability will be determined. LLCPK1 cells overexpressing individual PKC isozymes will be established and these cell lines will be used to delineate the role of individual isozymes in recovery following oxidant mediated injury. The third aim of the proposal is to study the effect of PKC activators and inhibitors on renal regeneration using a rat model of acute ischemic renal failure. Our preliminary data indicate that administration of PKC activators to rats pre-ischemia ameliorates the course of injury. These observations will be extended to test the effects of various PKC activators and inhibitors on renal function, morphology, cell proliferation, apoptosis and differentiation post- ischemia.