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.

项目摘要： 顺铂是许多固体器官癌类型的一线化学治疗，但其用法受到其限制 肾毒性。接受顺铂的患者中有30％发育急性肾脏损伤（AKI），这增加了 慢性肾脏疾病（CKD）和死亡率的风险。目前没有预防治疗选择或 治疗顺铂诱导的肾损伤（CDDP-KI）。顺铂诱导的肾脏损伤（CDDP-KI）已广泛 过去，我们的实验室和许多其他实验室使用单一的高剂量模型进行了研究。但是，患者是 通常用周期性低剂量的顺铂治疗，而不是单个高剂量。我们的实验室和其他实验室最近有 利用反复使用低剂量顺铂（RLDC）治疗的可能更临床相关的模型。在 这种新型号，小鼠每周接受4剂量的低剂量顺铂，并能够在6个月以上存活 治疗后。 RLDC模型可以分为两个阶段。重复的低级伤害阶段，该阶段 由四周的顺铂治疗组成，其特征是肾功能轻微下降， 小管细胞死亡，感染和纤维化发育的水平无关紧要。受伤阶段之后， 是一个进展阶段，其特征是持续注射，恶化的纤维化和 CKD的开发。该模型的两个阶段涉及的机制在很大程度上尚不清楚。 肾脏每个器官的线粒体密度最高，仅次于心脏。大多数 进行的重吸收发生在肾脏近端细胞上皮细胞（RPTECS）中。这些细胞高度 富含线粒体，依靠脂肪酸氧化（FAO）作为许多能源。顺铂曾经 在其他纤维化模型中可以看到会破坏FAO的粮农组织，而RPTEC中的粮农组织有缺陷。我们的初步数据 建议RLDC模型导致肾功能，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，脂肪生成，脂肪生成， 热生成和葡萄糖代谢。该研究建议将检查PGC-1α之间的关系 在RLDC模型的两个阶段，纤维化/CKD的表达和发展。我们假设这一点 在RLDC的损伤和/或进展阶段增加PGC-1α的表达将防止 肾脏损伤并分别防止向CKD进展。该假设将通过以下测试 具体目的：目标1：确定PGC-1α在RLDC模型的损伤阶段的作用。我们假设这一点 PGC-1α可免受RLDC诱导的肾损伤和纤维化倡议。我们将通过 在RLDC模型的损伤阶段过度表达并淘汰PGC-1α。目标2：确定角色 RLDC模型的进展阶段中PGC-1α的of。我们假设PGC-1α表达增加 顺铂给药后，将阻止RLDC诱导的纤维化和向CKD的进展。我们将过表达 RLDC剂量后的基因敲除PGC-1α。