Acute Kidney Injury by Cisplatin and Renoprotective Strategies

描述（由申请人提供）：顺铂是应用最广泛、最有效的化疗药物之一。然而，顺铂的使用与正常组织和器官，特别是肾脏的主要副作用相关，导致急性肾损伤（AKI）和肾功能衰竭。我们的研究目的是描述顺铂- aki的细胞信号传导机制，并确定有效的肾保护策略。然而，涉及多种因素的顺铂- aki是由肾小管细胞损伤和死亡以及组织损伤引起的。最近的研究揭示了顺铂- aki期间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，目前尚不清楚这些途径如何被调节和整合，从而导致令人印象深刻的肾脏病理。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，虽然PKC4的抑制对顺铂诱导的肾损伤有保护作用，但它在多种癌细胞系和卵巢肿瘤异种移植物体内增强了顺铂诱导的损伤和死亡。我们推测：1)PKC4是顺铂诱导肾损伤过程中细胞信号传导的关键调节因子；2)顺铂治疗过程中PKC4的激活涉及Src家族激酶，激活后PKC4可能调节p53和/或MAPK信号通路导致肾小管凋亡；3)抑制PKC4不仅可以保护肾脏，还可以增强顺铂在肿瘤中的化疗效果。我们将通过三个具体目标来验证这一假设：1)通过基因敲除模型阐明顺铂- aki期间PKC4在体内的激活，并确定其致病作用；2)阐明PKC4信号通路对顺铂- aki的影响；3)在荷瘤动物中，确定阻断PKC4是否能保护肾脏并增强顺铂的抗癌作用。该项目的完成不仅将获得AKI的新的机制见解，而且可能发现顺铂化疗期间新的有效的肾保护策略。

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. PUBLIC HEALTH RELEVANCE: Over a quarter of patients receiving cisplatin-based chemotherapy develop renal problems, leading to acute kidney injury and renal failure. No effective approaches are currently available to protect the kidneys in these cancer patients. By revealing a new signaling mechanism of cisplatin injury, this project will significantly advance the understanding of acute kidney injury associated with cisplatin chemotherapy. Moreover, it may discover a clinically applicable strategy for renoprotection that not only protects kidneys but may also enhance the chemotherapy effects of cisplatin in tumors.