Kidney Injury by Cisplatin and Renoprotective Strategies.

项目摘要 该项目的目标是研究顺铂化疗对肾脏的长期后遗症。 顺铂是目前应用最广泛、最有效的癌症治疗药物之一。然而，顺铂 化疗经常与肾脏的副作用有关，导致急性肾脏。 受伤和慢性肾脏问题。虽然过去的研究主要集中在顺铂造成的急性肾损伤上， 人们对顺铂治疗肾脏的慢性或长期影响知之甚少。一个主要的障碍 在研究顺铂的长期疗效方面，缺乏合适的动物模型。但我们和其他人 最近建立了反复小剂量顺铂治疗导致肾脏病变的小鼠模型 纤维化和慢性肾脏疾病，为研究慢性肾脏病的长期后遗症打开了大门 顺铂在肾脏的化疗。使用此模型，当前应用程序将研究自噬 在顺铂治疗后肾脏纤维化和慢性肾脏疾病中的作用。支持该应用程序 根据关键的初步发现：(1)顺铂治疗后，自噬伴随着 包括肾纤维化在内的慢性肾脏病理的发展；(2)自噬抑制剂在 顺铂治疗可预防慢性肾脏问题的发展；(3)肾小管细胞 可能以自噬依赖的方式产生和分泌特定的促纤维化因子；及。(4)在 上游，顺铂治疗导致P53和缺氧诱导因子-1(HIF-1)的激活，2 自噬的潜在监管者。基于这些发现，我们假设：顺铂治疗 导致P53和HIF-1的激活，从而诱导肾小管细胞的持续性自噬。 持续的自噬然后在这些肾小管细胞中触发分泌表型，以产生和 分泌促纤维化因子，激活间质成纤维细胞促进肾纤维化 进展为慢性肾脏病。我们将通过三个具体目标来检验这一假说：(1)检验假说 阻断自噬可能改善顺铂治疗后的肾纤维化和慢性肾脏病，而 加强肿瘤的化疗；(2)检验P53和/或HIF-1有助于 顺铂治疗后自噬激活、肾纤维化和慢性肾脏病；以及(3)检验假设 肾小管上皮细胞以自噬依赖的方式为成纤维细胞产生促纤维化因子 活化和纤维化形成。这项研究的完成将获得对长期- 顺铂治疗肾脏的长期副作用。此外，通过针对自噬和HIF-1， 这项工作可能会找到新的策略，不仅在顺铂治疗中保护肾脏，而且还能增强 肿瘤的化疗。

Project Summary 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.