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: 8042164
• 负责人: Zheng Dong
• 金额: $ 37.25万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042164
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adverse effects; Animal Model; Animals; Apoptosis; C57BL/6 Mouse; Cancer Biology; Cancer Patient; Cancer cell line; Cells; Cessation of life; Chronic; Cisplatin; Colonic Neoplasms; DNA Damage; Diuresis; Foundations; Genotype; Goals; Hydration status; In Vitro; Injury; Kidney; Kidney Failure; Knockout Mice; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Malignant Neoplasms; Malignant neoplasm of ovary; Modeling; Normal tissue morphology; Organ; Ovarian; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Platinum Compounds; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; TP53 gene; Testing; Therapeutic; Tissues; Tubular formation; Work; Xenograft Model; base; cancer cell; cancer therapy; cell injury; chemotherapy; clinically relevant; in vivo; inhibitor/antagonist; insight; kidney cell; knockout gene; nephrotoxicity; novel; ovarian neoplasm; response; rottlerin; src-Family Kinases; tumor; tumor xenograft

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.

描述（由申请人提供）：顺铂是最广泛使用和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，特别是肾脏中的主要副作用相关，导致急性肾损伤（阿基）和肾衰竭。本研究的目的是阐明顺铂-AKI的细胞信号传导机制，并确定有效的肾脏保护策略。然而，涉及多种因素的顺铂-AKI通过肾小管细胞损伤和死亡以及组织损伤而加速。最近的研究揭示了顺铂-AKI期间肾小管损伤的几种上游信号通路，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是如何调节和整合，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PKC 4在顺铂-AKI中的作用。值得注意的是，虽然PKC 4的抑制保护免受顺铂诱导的肾损伤，但它在多种癌细胞系中以及在体内卵巢肿瘤异种移植物中增强了顺铂诱导的损伤和死亡。我们假设：1）PKC 4是顺铂诱导的肾损伤期间细胞信号传导的关键调节剂; 2）顺铂治疗期间的PKC 4活化涉及Src家族激酶，并且在活化后，PKC 4可调节p53和/或MAPK信号传导通路以导致肾小管凋亡;和3）PKC 4的抑制不仅保护肾脏，而且还可增强顺铂在肿瘤中的化疗效果。我们将通过三个特定目的来验证这一假设：1）阐明顺铂-AKI期间体内PKC 4的激活，并通过使用基因敲除模型确定其致病作用; 2）描述导致顺铂-AKI的PKC 4信号通路; 3）确定阻断PKC 4是否可以保护肾脏并增强顺铂在荷瘤动物中的抗癌作用。该项目的完成不仅将获得阿基的新机制见解，还可能发现一种新的有效的顺铂化疗期间肾保护策略。 公共卫生相关性：超过四分之一接受顺铂化疗的患者会出现肾脏问题，导致急性肾损伤和肾衰竭。目前还没有有效的方法来保护这些癌症患者的肾脏。通过揭示顺铂损伤的新信号机制，该项目将显著推进对顺铂化疗相关急性肾损伤的理解。此外，它可能会发现一种临床上适用的肾脏保护策略，不仅保护肾脏，而且还可能增强顺铂在肿瘤中的化疗效果。