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.

项目总结： 顺铂是许多实体器官癌的一线化疗药物，但其用途受到其限制。 肾毒性。30%接受顺铂治疗的患者发展为急性肾损伤(AKI)，其发病率增加 慢性肾脏疾病(CKD)和死亡率的风险。目前没有治疗选择来预防或 治疗顺铂所致肾损伤(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的高剂量模型进行了研究。然而，患者是 通常采用周期性的低剂量顺铂治疗，而不是单一的高剂量。我们的实验室和其他实验室最近 利用重复的低剂量顺铂(RLDC)治疗开发了一种潜在的更具临床相关性的模型。在……里面 这种新的模型，小鼠每周接受4次低剂量顺铂治疗，能够存活6个月以上 后处理。RLDC模型可以分为两个阶段。反复低水平损伤阶段，这是 包括四周的顺铂治疗，其特点是肾功能轻度下降， 肾小管上皮细胞死亡、炎症和纤维化发展的程度不显著。在伤病阶段之后，有 是一个进展期，其特征是持续的炎症，加重的纤维化，以及 CKD的发展。这一模型的两个阶段所涉及的机制在很大程度上仍不清楚。这个 肾脏是每个器官中线粒体密度最高的，仅次于心脏。大多数人 重吸收发生在肾近端小管上皮细胞(RPTECs)。这些细胞是高度 富含线粒体，依赖脂肪酸氧化(FAO)作为其多种能量来源。顺铂已经被 显示扰乱了粮农组织，在其他纤维化模型中可以看到粮农组织在RPTEC中存在缺陷。我们的初步数据 提示RLDC模型可导致肾功能、线粒体含量和PGC-1α的降低。PGC- 1α是线粒体生物发生、脂肪酸氧化、脂肪生成、 产热作用和葡萄糖代谢。这项研究提案将检验pGC-1α与 纤维化/慢性肾脏病在RLDC模型的两个阶段的表达和发展。我们假设 在肾小管树突状细胞损伤和/或进展期增加PGC-1α的表达将对 肾脏损伤和防止进展为CKD。这一假设将用以下方法进行检验 具体目的：目的1：确定前列腺素C-1α在肾小管树突状细胞损伤过程中的作用。我们假设 PGC-1α对rLDC诱导的肾脏损伤和纤维化的启动具有保护作用。我们将通过以下方式验证这一假设 在大鼠肾小管树突状细胞损伤阶段过表达并敲除pGC-1α。目标2：确定角色 RLDC模型进展期pGC-1α的表达。我们假设pGC-1α表达增加 顺铂给药后可防止RLDC诱导的纤维化和进展为CKD。我们将过度表达和 RLDC给药后，敲除pgc-1α。