Role of Rho Kinase in Diabetic Nephropathy

Rho 激酶在糖尿病肾病中的作用

• 批准号: 9210083
• 负责人: FARHAD R DANESH
• 金额: $ 34.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210083
• 关键词: Address; Apoptosis; Biological; Cells; Cellular Metabolic Process; Co-Immunoprecipitations; Complex; Coupled; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dictyostelium discoideum dynamin A; Disease; Dynamin; Dynamin I; End stage renal failure; Endothelial Cells; Event; Exhibits; Experimental Models; Functional disorder; Future; Genetic; Glucose; Goals; Impairment; Innovative Therapy; Kidney; Lead; Mass Spectrum Analysis; Mediating; Metabolic Diseases; Mitochondria; Molecular; Morphology; Mus; Pharmacology; Phenotype; Phosphorylation; Phosphorylation Site; Process; Protein Kinase; Proteins; Publishing; ROCK1 gene; Recruitment Activity; Rho-associated kinase; Role; Serine; Serine Phosphorylation Site; Signal Transduction; Site; Stimulus; Testing; Time; base; cell type; diabetic; expectation; experimental study; gain of function; genetic approach; in vivo; inhibitor/antagonist; insight; interest; mitochondrial dysfunction; new therapeutic target; podocyte; prevent; protein protein interaction; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Diabetic nephropathy represents the primary cause of end stage renal disease (ESRD) in the US, underscoring the need for innovative therapies for preventing its progression. We are interested in understanding the cellular and molecular mechanisms that govern mitochondrial dysfunction in the diabetic milieu with the expectation that understanding of these processes will expose potential disease mechanisms and therapeutic targets in diabetic nephropathy. The present proposal is based on our recent published observation, indicating that ROCK1-mediated mitochondrial fragmentation is essential for prompting mitochondrial dysfunction in podocytes and glomerular endothelial cells in the diabetic milieu. A detailed understanding of mechanisms that govern mitochondrial fission in the kidney remains incomplete and therapeutic targets based on these mechanisms do not exist. Because dynamin-related protein-1 (Drp1) is an integral part in regulating mitochondrial fission, we have focused on investigating the functions of ROCK1 on Drp1 translocation to the mitochondria resulting in mitochondrial fragmentation and cell apoptosis. We have been guided by our recent published observations that ROCK1 mediates high glucose-induced mitochondrial fragmentation by promoting Drp1 recruitment to the mitochondria. Deletion of ROCK1 in db/db diabetic mice prevented mitochondrial fission, whereas podocyte-specific constitutively active (cA)-ROCK1 mice exhibited increased mitochondrial fission. Importantly, we found that ROCK1 triggers mitochondrial fission by phosphorylating Drp1 at serine 600 residue. These findings provide compelling initial evidence into the unexpected role of ROCK1 in a signaling cascade that regulates mitochondrial dynamics, and represents a therapeutic target that might be useful in preventing diabetic kidney disease. Given these results and additional preliminary data presented in this application, this project will address the hypothesis that phosphorylation of Drp1 is a key feature of mitochondria dysfunction in diabetic nephropathy. The results of this study will provide important new insights into the role of mitochondrial morphology in the development of diabetic nephropathy, and may lead to novel therapeutic targets for the future treatment of diabetic kidney disease.

描述（由申请人提供）：糖尿病肾病是美国终末期肾病（ESRD）的主要原因，强调了预防其进展的创新疗法的必要性。我们有兴趣了解糖尿病环境中线粒体功能障碍的细胞和分子机制，并期望了解这些过程将揭示糖尿病肾病的潜在疾病机制和治疗靶点。目前的建议是基于我们最近发表的观察，表明ROCK 1介导的线粒体断裂是必不可少的，促进线粒体功能障碍的足细胞和肾小球内皮细胞在糖尿病环境。对肾脏中线粒体分裂的机制的详细理解仍然不完整，并且基于这些机制的治疗靶点不存在。由于动力蛋白相关蛋白-1（dynamin-related protein-1，Drp 1）是调节线粒体分裂的重要组成部分，因此我们重点研究了ROCK 1在Drp 1转位至线粒体导致线粒体断裂和细胞凋亡中的作用。我们最近发表的观察结果表明，ROCK 1通过促进Drp 1向线粒体的募集来介导高糖诱导的线粒体片段化。db/db糖尿病小鼠中ROCK 1的缺失阻止了线粒体分裂，而足细胞特异性组成型活性（cA）-ROCK 1小鼠表现出线粒体分裂增加。重要的是，我们发现ROCK 1通过磷酸化Drp 1的丝氨酸600残基来触发线粒体分裂。这些发现为ROCK 1在调节线粒体动力学的信号级联中的意想不到的作用提供了令人信服的初步证据，并代表了可能有助于预防糖尿病肾病的治疗靶点。鉴于这些结果和本申请中提供的其他初步数据，该项目将解决Drp 1磷酸化是糖尿病肾病线粒体功能障碍的关键特征的假设。这项研究的结果将为线粒体形态在糖尿病肾病发展中的作用提供重要的新见解，并可能为糖尿病肾病的未来治疗提供新的治疗靶点。