Kidney Injury by Cisplatin and Renoprotective Strategies.

顺铂引起的肾损伤和肾脏保护策略。

基本信息

批准号：
10356820
负责人：
Zheng Dong
金额：
$ 41.84万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356820
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Animal Model Animals Antineoplastic Agents Autophagocytosis Autophagosome Cancer Patient Cell physiology Cells Chronic Chronic Kidney Failure Cisplatin Conditioned Culture Media Development Dose Fibroblasts Goals Injury Injury to Kidney Kidney Knockout Mice Lead Long-Term Effects Longitudinal Studies Modeling Mus Normal tissue morphology Organ Pathogenesis Pathology Pharmaceutical Preparations Pharmacology Phenotype Positioning Attribute Production Profibrotic signal Regulation Renal tubule structure Reporting Research Role TP53 gene Testing Tubular formation Work base cancer therapy chemotherapy fibrogenesis hypoxia inducible factor 1 inhibition of autophagy inhibitor insight interstitial kidney fibrosis knockout gene long-term sequelae mouse model nephrotoxicity new therapeutic target novel strategies prevent side effect tool tumor

项目摘要

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.

项目概要该项目的目标是研究顺铂化疗对肾脏的长期后遗症。顺铂是最广泛使用和最有效的癌症治疗药物之一。然而，顺铂化疗经常与肾脏产生不良副作用相关，导致急性肾衰竭受伤和慢性肾脏问题。虽然过去的工作重点是顺铂引起的急性肾损伤，关于顺铂治疗对肾脏的慢性或长期影响知之甚少。一个主要障碍在研究顺铂的长期效应方面缺乏合适的动物模型。但我们和其他人最近建立了重复低剂量顺铂治疗的小鼠模型，该模型导致肾病纤维化和慢性肾脏疾病，为研究长期后遗症打开了大门肾脏顺铂化疗。使用该模型，当前的应用程序将研究自噬顺铂治疗后的肾纤维化和慢性肾病。支持申请通过关键的初步发现：（1）顺铂治疗后，自噬被诱导慢性肾脏病变的发展，包括肾纤维化； (2) 之后给予自噬抑制剂顺铂治疗可以预防慢性肾脏问题的发展； (3)肾小管细胞可能以自噬依赖性方式产生和分泌特定的促纤维化因子； (4) 在在上游，顺铂治疗导致 p53 和缺氧诱导因子 1 (HIF-1) 的激活，两个自噬的潜在调节因子。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持续自噬。然后，持续的自噬会在这些管状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 CKD。我们将通过三个具体目标来检验这个假设：（1）检验以下假设：阻断自噬可能会改善顺铂治疗后的肾纤维化和 CKD，而加强肿瘤化疗； (2)检验p53和/或HIF-1有助于的假设顺铂治疗后自噬激活、肾纤维化和 CKD； (3) 检验假设肾小管细胞以自噬依赖性方式为成纤维细胞产生促纤维化因子活化和纤维形成。研究的完成将对长期的问题获得重要的新见解。顺铂治疗对肾脏的长期副作用。此外，通过靶向自噬和 HIF-1，这项工作可能会找到新的策略，不仅可以在顺铂治疗中保护肾脏，还可以增强肿瘤化疗。