The role of PGC-1alpha in repeated low-dose cisplatin-induced kidney injury and the progression to chronic kidney disease

PGC-1α 在重复低剂量顺铂诱导的肾损伤和慢性肾病进展中的作用

• 批准号: 10640822
• 负责人: Andrew Orwick
• 金额: $ 0.6万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640822
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Aftercare; Age Months; Automobile Driving; Bioenergetics; Biogenesis; Biopsy; Cancer Patient; Carcinoma; Cell Death; Cells; Cellular biology; Chronic Kidney Failure; Cisplatin; Clinic; Data; Development; Dose; Dose Limiting; Effectiveness; Energy-Generating Resources; Epithelial Cells; Excision; Fibrosis; Generations; Genetic Transcription; Heart; Human; Inflammation; Injury; Injury to Kidney; Kidney; Knock-out; Knowledge; LCN2 gene; Literature; Mediator; Medical; Mitochondria; Modeling; Mus; Organ; Oxygen Consumption; Patients; Periodicals; Pharmaceutical Preparations; Phase; Platinum; Prevention; Process; Proximal Kidney Tubules; Publishing; Renal function; Research Proposals; Risk; Rodent Model; Role; Solid; Solid Neoplasm; Testing; Therapeutic; Therapeutic Uses; Thermogenesis; Tissues; Translations; absorption; cancer type; clinically relevant; density; fatty acid oxidation; glucose metabolism; innovation; kidney cortex; kidney fibrosis; lipid biosynthesis; metabolomics; mortality; mouse model; nephrotoxicity; new therapeutic target; novel; overexpression; prevent; renal damage; therapeutic target

Project Summary: Cisplatin is a first-line chemotherapeutic for many solid organ cancer types, but its usages are limited by its nephrotoxicity. Thirty percent of patients who receive cisplatin develop acute kidney injury (AKI), which increases the risk of chronic kidney disease (CKD) and mortality. There are currently no treatment options to prevent or treat cisplatin-induced kidney injury (CDDP-KI). Cisplatin-induced kidney injury (CDDP-KI) has been extensively investigated in the past by our lab and many other labs using a single, high-dose model. However, patients are typically treated with periodic low doses of cisplatin, not a single high dose. Our lab and others have recently developed a potentially more clinically relevant model utilizing repeated low-dose cisplatin (RLDC) treatment. In this new model, mice receive 4 weekly doses of low dose cisplatin and are able to survive more than 6-months post-treatment. The RLDC model can be broken up into two phases. The repeated low-level injury phase, which consists of the four weeks of cisplatin treatment and is characterized by a mild decline in kidney function, insignificant levels of tubule cell death, inflammation, and development of fibrosis. After the injury phase, there is a progression phase that is characterized by persistent inflammation, exacerbated fibrosis, and the development of CKD. The mechanisms involved in both phases of this model remain largely unknown. The kidneys have the highest density of mitochondria per organ, second only to the heart. The majority of the reabsorption performed occurs in the renal proximal tubule epithelial cells (RPTECs). These cells are highly enriched in mitochondria and rely on fatty acid oxidation (FAO) as their many energy source. Cisplatin has been shown to disrupt FAO, and defective FAO in RPTEC is seen in other models of fibrosis. Our preliminary data suggest that the RLDC model causes a decrease in renal function, mitochondrial content, and PGC-1α. PGC- 1α is a master transcriptional regulator of mitochondrial biogenesis, fatty acid oxidation, lipogenesis, thermogenesis, and glucose metabolism. This research proposal will examine the relationship between PGC-1α expression and the development of fibrosis/CKD in both phases of the RLDC model. We hypothesize that increasing PGC-1α expression during the injury and/ or progression phases of RLDC will protect against kidney injury and prevent progression to CKD, respectively. This hypothesis will be tested with the following specific aims: Aim 1: Determine the role of PGC-1α in the injury phase of the RLDC model. We hypothesize that PGC-1α protects from RLDC-induced kidney injury and initiation of fibrosis. We will test this hypothesis by overexpressing and knocking out PGC-1α during the injury phase of the RLDC model. Aim 2: Determine the role of PGC-1α in the progression phase of the RLDC model. We hypothesize that increased PGC-1α expression following cisplatin dosing will prevent RLDC-induced fibrosis and progression to CKD. We will overexpress and knockout PGC-1α following RLDC dosing.

项目概要： 顺铂是许多实体器官癌类型的一线化疗药物，但其用途受到其本身的限制。 肾毒性。接受顺铂治疗的患者中有 30% 会出现急性肾损伤 (AKI)，这会增加 慢性肾病（CKD）和死亡的风险。目前没有治疗方案可以预防或 治疗顺铂引起的肾损伤（CDDP-KI）。顺铂诱导的肾损伤（CDDP-KI）已被广泛研究 我们的实验室和许多其他实验室过去使用单一高剂量模型进行了研究。然而，患者是 通常采用周期性低剂量顺铂治疗，而不是单次高剂量顺铂治疗。我们的实验室和其他人最近 利用重复低剂量顺铂（RLDC）治疗开发了一种可能更具临床相关性的模型。在 在这个新模型中，小鼠每周接受 4 剂低剂量顺铂，并且能够存活超过 6 个月 治疗后。 RLDC 模型可以分为两个阶段。重复的低度损伤阶段， 由四个星期的顺铂治疗组成，其特点是肾功能轻度下降， 肾小管细胞死亡、炎症和纤维化发展水平不显着。损伤阶段结束后， 是一个进展阶段，其特征是持续炎症、加剧纤维化和 CKD 的发展。该模型两个阶段所涉及的机制仍然很大程度上未知。这 每个器官中肾脏的线粒体密度最高，仅次于心脏。大多数 重吸收发生在肾近曲小管上皮细胞（RPTEC）中。这些细胞高度 富含线粒体，并依赖脂肪酸氧化（FAO）作为其许多能量来源。顺铂已 研究显示 RPTEC 会破坏FAO，而在其他纤维化模型中也可以看到 RPTEC 中存在缺陷的FAO。我们的初步数据 表明 RLDC 模型导致肾功能、线粒体含量和 PGC-1α 下降。 PGC- 1α 是线粒体生物发生、脂肪酸氧化、脂肪生成的主要转录调节因子， 生热作用和葡萄糖代谢。本研究计划将探讨 PGC-1α 之间的关系 RLDC 模型两个阶段中纤维化/CKD 的表达和发展。我们假设 在 RLDC 损伤和/或进展阶段增加 PGC-1α 表达将预防 分别预防肾损伤和预防进展为 CKD。该假设将通过以下内容进行检验 具体目标： 目标 1：确定 PGC-1α 在 RLDC 模型损伤阶段的作用。我们假设 PGC-1α 可防止 RLDC 诱导的肾损伤和纤维化的发生。我们将通过以下方式检验这个假设 在 RLDC 模型的损伤阶段过度表达并敲除 PGC-1α。目标 2：确定角色 RLDC 模型进展阶段的 PGC-1α。我们假设 PGC-1α 表达增加 顺铂给药后可预防 RLDC 诱导的纤维化和进展为 CKD。我们会过度表达并 RLDC 给药后敲除 PGC-1α。