Acute Kidney Injury by Cisplatin and Renoprotective Strategies

 描述(申请人提供)：顺铂是应用最广泛和最有效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相关，导致超过25%的患者出现急性肾损伤(顺铂-AKI)。顺铂-AKI的作用机制尚不清楚，也没有有效的肾脏保护方法。我们最近揭示了PKCδ在顺铂-AKI中的关键作用，值得注意的是，抑制PKCδ不仅可以保护肾脏，还可以增强顺铂在肿瘤中的化疗效果。尽管有这些发现，但在很大程度上还不清楚抑制PKCδ能如何保护 肾脏，同时杀死癌细胞。我们已经证明了顺铂-AKI的自噬诱导及其在肾脏保护中的关键作用。此外，还提出了通过自噬来移除受损线粒体的有丝分裂。从机制上讲，我们的初步工作支持p53和PKCδ参与顺铂-AKI过程中的自噬调节。我们假设：1)有丝分裂吞噬在顺铂-AKI过程中被激活，并在很大程度上解释了自噬的肾脏保护作用；2)P53有助于诱导顺铂-AKI的自噬，而PKCδ起自噬抑制作用；以及3)抑制PKCδ可能通过促进自噬而在顺铂化疗过程中保护肾脏。为了验证这一假设，我们建议：1)阐明有丝分裂吞噬作为顺铂-AKI自噬的一种保护机制；2)确定P53在顺铂-AKI中促进自噬的作用；3)描述PKCδ在顺铂-AKI中的自噬抑制作用；以及4)通过分析PKCδ抑制在自噬抑制和非抑制小鼠中的作用，检验PKCδ抑制通过促进自噬来保护肾脏的假说。这项研究的完成不仅将对自噬在肾脏发病机制中的保护和调控有重要的意义，而且还将阐明自噬作为PKCδ抑制的肾脏保护作用的机制，为癌症患者化疗期间的肾脏保护提供一种新的治疗策略。

 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.