Acute Kidney Injury by Cisplatin and Renoprotective Strategies

顺铂引起的急性肾损伤和肾脏保护策略

• 批准号: 9324777
• 负责人: Zheng Dong
• 金额: $ 5.04万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324777
• 关键词: Accounting; Acute Renal Failure with Renal Papillary Necrosis; Adverse effects; Autophagocytosis; Cancer Patient; Cells; Cisplatin; Diuresis; FRAP1 gene; Figs - dietary; Functional disorder; Funding; Goals; Health; Hydration status; Injury; Kidney; Knockout Mice; Malignant Neoplasms; Mediating; Mitochondria; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Play; Positioning Attribute; Regulation; Renal tubule structure; Reporter; Research; Role; TP53 gene; Testing; Therapeutic; Tubular formation; Up-Regulation; Wild Type Mouse; Work; base; cancer cell; cancer therapy; chemotherapy; inhibitor/antagonist; insight; killings; knockout gene; nephrotoxicity; novel; novel therapeutics; parkin gene/protein; protective effect; tool; tumor

 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.

 描述（由适用提供）：顺铂是最广泛使用和最潜在的癌症治疗药物之一。然而，顺铂的使用与肾毒性的主要副作用有关，导致超过25％的患者在25％的患者中导致急性肾损伤（Cisplatin-Aki）。顺铂-Aki的机制仍然不清楚，有效的肾脏保护方法不可用。我们最近揭示了PKCδ在顺铂-Aki中的关键作用，并且明显地抑制PKCδ不仅可以保护肾脏，而且还可以增强顺铂在肿瘤中的化学疗法作用。尽管有这些发现，但尚不清楚PKCδ如何保护 肾脏，同时杀死癌细胞。我们已经证明了顺铂-aki的自噬及其在肾脏保护中的关键作用。此外，已经提出了通过自噬去除线粒体受损的线粒体。从机械上讲，我们的初步工作支持顺铂-AKI期间p53和PKCδ在自噬调节中的参与。我们假设：1）在顺铂-aki期间激活线粒体，并在很大程度上是为了自噬的重新保护作用； 2）p53有助于顺铂-Aki自噬诱导，而PKCδ起自噬抑制作用； 3）抑制PKCδ可以通过增强自噬化疗期间在顺铂化疗期间保护肾脏。为了检验这一假设，我们建议：1）阐明线粒体作为顺铂-Aki自噬的受保护机制； 2）确定p53在顺铂-aki中的自噬促进作用； 3）描述PKCδ在顺铂-aki中的自噬作用； 4）检验以下假设：PKCδ抑制通过分析PKCΔ抑制在自噬抑制和非抑制小鼠中的影响来保护肾脏。这项研究的完成不仅将获得对肾脏发病机理自噬保护和调节的重要见解，而且还将阐明自噬是PKCδ抑制的重新保护作用的机制，这表明癌症患者化学治疗期间肾脏保护的新型热策略。