Acute Kidney Injury by Cisplatin and Renoprotective Strategies

说明(申请人提供)：顺铂是应用最广泛、药效最强的化疗药物之一。然而，顺铂的使用与正常组织和器官的主要副作用有关，特别是肾脏，导致急性肾损伤(AKI)和肾功能衰竭。我们研究的目的是阐明顺铂-AKI的细胞信号机制，并找出有效的肾脏保护策略。顺铂-AKI涉及多个因素，但它是由肾小管细胞损伤和死亡以及组织损伤引起的。最近的研究已经揭示了顺铂-AKI过程中肾小管损伤的几个上游信号通路，包括Src、MAPK、p53和快速DNA损伤反应。然而，目前尚不清楚这些通路是如何调节和整合，从而导致令人印象深刻的肾脏病理的。我们的初步研究首次证明了PKC4在顺铂-AKI中的作用。值得注意的是，在抑制PKC4对顺铂诱导的肾脏损伤具有保护作用的同时，它增加了顺铂在多种癌细胞系中的损伤和死亡，也增加了体内卵巢肿瘤异种移植瘤的损伤和死亡。我们推测：1)PKC4在顺铂诱导的肾损伤中是细胞信号转导的关键调节因子；2)顺铂治疗过程中PKC4的激活涉及一个Src家族的激酶，激活后，PKC4可能调节P53和/或MAPK信号通路，导致肾小管细胞凋亡；3)抑制PKC4不仅可以保护肾脏，还可以增强顺铂对肿瘤的化疗效果。我们将通过三个特定的目标来验证这一假说：1)阐明顺铂-AKI过程中体内PKC4的激活，并通过基因敲除模型确定其致病作用；2)描绘参与顺铂-AKI的PKC4信号通路；以及3)确定阻断PKC4是否可以保护肾脏并增强顺铂对荷瘤动物的抗癌作用。该项目的完成不仅将获得AKI的新机制见解，还可能发现一种新的有效策略，用于顺铂为主的化疗期间的肾脏保护。

DESCRIPTION (provided by applicant): Cisplatin is one of the most widely used and most potent chemotherapy drugs. However, the use of cisplatin is associated with major side effects in normal tissues and organs, especially the kidneys, leading to acute kidney injury (AKI) and renal failure. The goal of our research is to delineate the cell signaling mechanism of cisplatin-AKI and identify effective strategies for renoprotection. Cisplatin-AKI, involving multiple factors, is nevertheless precipitated by renal tubular cell injury and death, and tissue damage. Recent research has revealed several upstream signaling pathways in tubular damage during cisplatin-AKI, including Src, MAPK, p53 and a rapid DNA damage response. However, it remains unclear how these pathways are regulated and integrated to result in an impressive renal pathology. Our preliminary studies demonstrated the first evidence for a role of PKC4 in cisplatin-AKI. Notably, while inhibition of PKC4 protected against cisplatin-induced kidney injury, it enhanced cisplatin-induced injury and death in multiple cancer cells lines and also in vivo in ovarian tumor xenografts. We hypothesize that: 1) PKC4 is a key regulator of cell signaling during cisplatin-induced kidney injury; 2) PKC4 activation during cisplatin treatment involves a Src family kinase and after being activated, PKC4 may regulate p53 and/or MAPK signaling pathways to result in renal tubular apoptosis; and 3) inhibition of PKC4 not only protects kidneys but can also enhance the chemotherapy effects of cisplatin in tumors. We will test this hypothesis by three Specific Aims: 1) elucidate PKC4 activation in vivo during cisplatin-AKI and establish its pathogenic role by using gene knockout models; 2) delineate the PKC4 signaling pathway that contributes to cisplatin-AKI; and 3) determine if blocking PKC4 can protect kidneys and enhance the anti-cancer effect of cisplatin in tumor-bearing animals. Completion of the project will not only gain novel mechanistic insights of AKI but may also discover a new and effective strategy for renoprotection during cisplatin-based chemotherapy.