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NADPH oxidases-derived ROS downregulate TRPC6 in mesangial cells in diabetes

NADPH 氧化酶衍生的 ROS 下调糖尿病肾小球膜细胞中的 TRPC6

基本信息

批准号：
8291905
负责人：
RONG MA
金额：
$ 28.04万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291905
关键词：
Address Agonist Animal Model Applications Grants Area Blood Vessels Cell Culture Techniques Cell surface Characteristics Clinical Treatment Complications of Diabetes Mellitus Development Diabetes Mellitus Diabetic Nephropathy Down-Regulation Drug Design Enzymes Extracellular Matrix Family Focal Segmental Glomerulosclerosis Generations Genes Genetic Transcription Glomerular Capillary Glomerular Filtration Rate Glomerular Mesangial Cell Glucose Homologous Gene Human Hyperglycemia Hypertrophy Impairment In Vitro Kidney Kidney Diseases Link Measures Mediating Messenger RNA Molecular NADP NADPH Oxidase Oxidative Stress Pathway interactions Phagocytes Phenotype Physiological Play Property Protein Isoforms Proteins Rattus Reactive Oxygen Species Regulation Reporting Rest Role Series Signal Pathway Signal Transduction Smooth Muscle Myocytes Source Staging Streptozocin Surface System Testing Vascular Smooth Muscle Vasoconstrictor Agents Work arteriole cell type diabetic diabetic rat hemodynamics in vivo interest kidney cortex mRNA Expression member mesangial cell novel podocyte protein expression receptor response

项目摘要

Project Summary At the early stage of diabetes, the GFR becomes supernormal. This early hemodynamic phenotype provokes the subsequent demise of a diabetic kidney. The diabetic hyperfiltration is derived from a combined decreased responsiveness of both the renal afferent arterioles and the MCs to vasoconstrictors. Reduced Ca2+ influx is a critical contributing factor to the hypocontractility of MCs in diabetes. However, the underlying mechanism(s) are still poorly understood. Furthermore, emerging evidence implicates NADPH oxidases-, particularly Nox4-derived ROS in the development of diabetic nephropathy. However, the underlying mechanism and downstream signaling pathway are at a large extent unknown. This proposal seeks to test the hypothesis that TRPC6 protein, a newly found Ca2+ permeable channel protein, contributes to the contractile function of MCs and downregulation of the protein in MCs by NADPH oxidases-mediated ROS results in diabetic hyperfiltration. Three specific aims will be tested. (1) Determine whether TRPC6 regulates contractile function and Ca2+ signaling of glomerular MCs in in vitro, ex vivo, and in vivo systems. (2) Explore the postulate that ROS mediate downregulation of TRPC6 protein expression in glomerular MCs by diabetes in an in vitro (cultured MCs) and in vivo animal model. (3) Determine the source of ROS, focusing on NADPH oxidases, and the molecules downstream ROS, focusing on NF-¿B, in the signaling pathway of TRPC6 downregulation by diabetes. The information obtained from this novel study will advance our current understanding of the molecular mechanism for the development of diabetic nephropathy, and therefore provides a rationale for drug design and clinical treatment of diabetes by intervening in the proposed pathway. In addition, TRPC6 has been found to play an important role in a variety of cell types. However, regulation of TRPC6 channel, particularly at gene transcriptional level, is unknown currently. The proposed studies will tackle this important issue by investigating if ROS repress TRPC6 gene transcription through the NF-¿B mechanism. Thus, this project is of interest to both ROS and TRPC6 fields.

项目总结