Acute Kidney Injury by Cisplatin and Renoprotective Strategies

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 DESCRIPTION (provided by applicant): Cisplatin is one of the most widely used and most potent cancer therapy drugs. However, the use of cisplatin is associated with a major side-effect of nephrotoxicity, resulting in acute kidney injury (cisplatin-AKI) in over 25% of patients. The mechanism of cisplatin-AKI remains unclear and effective renoprotective approaches are not available. We have recently unveiled a critical role of PKCδ in cisplatin-AKI and, remarkably, inhibition of PKCδ not only protects kidneys but can also enhance the chemotherapy effect of cisplatin in tumors. Despite these findings, it is largely unclear how PKCδ inhibition can protect kidneys, while killing cancer cells. We have demonstrated autophagy induction in cisplatin-AKI and its critical role of kidney protection. Moreover, mitophagy that removes damaged mitochondria via autophagy has been suggested. Mechanistically, our preliminary work supports the involvement of p53 and PKCδ in autophagy regulation during cisplatin-AKI. We hypothesize that: 1) mitophagy is activated during cisplatin-AKI and accounts largely for the renoprotective effect of autophagy; 2) p53 contributes to autophagy induction in cisplatin-AKI, whereas PKCδ plays an autophagy suppressive role; and 3) inhibition of PKCδ may protect kidneys during cisplatin chemotherapy by enhancing autophagy. To test this hypothesis, we propose to: 1) elucidate mitophagy as a protective mechanism of autophagy in cisplatin-AKI; 2) determine the autophagy-promoting role of p53 in cisplatin-AKI; 3) delineate the autophagy-suppressing role of PKCδ in cisplatin-AKI; and 4) test the hypothesis that PKCδ inhibition protects kidneys through enhancing autophagy by analyzing the effects of PKCδ inhibition in autophagy-suppressed and non-suppressed mice. Completion of the research will not only gain significant insights into autophagy protection and regulation in renal pathogenesis, but will also elucidate autophagy as a mechanism of the renoprotective effect of PKCδ inhibition, suggesting a novel therapeutic strategy for kidney protection during chemotherapy in cancer patients.