The goal of this project is to investigate the long-term sequelae of cisplatin chemotherapy in kidneys. Cisplatin is one of the most widely used and most potent cancer therapy drugs. However, cisplatin chemotherapy is frequently associated with adverse side-effects in kidneys, resulting in acute kidney injury and chronic kidney problems. While the past work has focused on acute kidney injury by cisplatin, very little is known about the chronic or long-term effect of cisplatin treatment in kidneys. A major hurdle in studying the long-term effect of cisplatin is the lack of appropriate animal models. But we and others have recently established the mouse model of repeated low dose cisplatin treatment that leads to renal fibrosis and chronic kidney disease, opening the door to the research of the long-term sequelae of cisplatin chemotherapy in kidneys. Using this model, the current application will investigate autophagy in renal fibrosis and chronic kidney disease following cisplatin treatment. The application is supported by critical preliminary findings: (1) Following cisplatin treatment, autophagy is induced along with the development of chronic kidney pathologies including renal fibrosis; (2) Autophagy inhibitors given after cisplatin treatment can prevent the development of chronic kidney problems; (3) Renal tubular cells may produce and secret specific profibrotic factors in an autophagy-dependent manner; and (4) At the upstream, cisplatin treatment leads to the activation of p53 and hypoxia-inducible factor-1 (HIF-1), two potential regulators of autophagy. Based on these findings, we hypothesize that: Cisplatin treatment leads to the activation of p53 and HIF-1, which induce persistent autophagy in renal tubular cells. Persistent autophagy then triggers a secretory phenotype in these tubular cells for the production and secretion of profibrotic factors, which activate interstitial fibroblasts to promote renal fibrosis and the progression to CKD. We will test this hypothesis by three Specific Aims: (1) test the hypothesis that blockade of autophagy may ameliorate renal fibrosis and CKD following cisplatin treatment, while enhancing chemotherapy in tumors; (2) test the hypothesis that p53 and/or HIF-1 contribute to autophagy activation, renal fibrosis and CKD following cisplatin treatment; and (3) test the hypothesis that renal tubular cells produce profibrotic factors in an autophagy-dependent manner for fibroblast activation and fibrogenesis. Completion of the research will gain significant new insights into the long- term side-effects of cisplatin treatment in kidneys. Moreover, by targeting autophagy and HIF-1, the work may identify novel strategies that not only protect kidneys in cisplatin treatment but also enhance chemotherapy in tumors.
(Relevance) Cisplatin, a widely used chemotherapy drug, elicits both acute and chronic side-effects in kidneys in cancer patients. This application will investigate autophagy as a cause of the chronic side-effect of cisplatin. Completion of the work will not only advance the understanding of the chronic kidney problems following cisplatin chemotherapy, but may also identify novel therapeutic targets.
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