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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：
8581827
负责人：
RONG MA
金额：
$ 0.15万
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/8581827
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.

项目摘要在糖尿病的早期阶段，GFR变得异常。这种早期血流动力学表型会导致糖尿病肾病的死亡糖尿病超滤是由肾传入小动脉和MC对血管收缩剂的反应性降低。还原Ca 2 + 内流是糖尿病中MC收缩力低下的关键因素。但是，底层机制仍然知之甚少。此外，新出现的证据表明NADPH氧化酶，特别是Nox 4衍生的ROS在糖尿病肾病的发展中的作用。然而，底层机制和下游信号通路在很大程度上是未知的。这项建议旨在测试 TRPC 6蛋白是一种新发现的钙通道蛋白， MCs的功能和通过NADPH氧化酶介导的ROS下调MCs中的蛋白质导致糖尿病高滤过将测试三个具体目标。(1)确定TRPC 6是否调节收缩体外、离体和体内系统中肾小球MCs的功能和Ca 2+信号传导。(2)探索假设 ROS介导糖尿病大鼠肾小球系膜细胞TRPC 6蛋白表达下调（培养的MC）和体内动物模型。(3)确定ROS的来源，重点是NADPH氧化酶，在TRPC 6下调的信号通路中，ROS下游分子，集中在NF-B上，糖尿病从这项新研究中获得的信息将促进我们目前对糖尿病肾病发生的分子机制，因此为药物治疗提供了理论基础设计和临床治疗糖尿病的干预提出的途径。此外，TRPC 6还发现在多种细胞类型中发挥重要作用。然而，TRPC 6通道的调节，特别是在基因转录水平，目前尚不清楚。拟议的研究将通过以下方式处理这一重要问题：研究ROS是否通过NF-B机制抑制TRPC 6基因转录。因此，该项目是对ROS和TRPC 6领域都感兴趣。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.

DOI：
10.1089/nat.2014.0505
发表时间：
2015-03
期刊：
Nucleic acid therapeutics
影响因子：
4
作者：
J. Zuckerman;A. Gale;Peiwen Wu;R. Ma;Mark E. Davis
通讯作者：
J. Zuckerman;A. Gale;Peiwen Wu;R. Ma;Mark E. Davis

The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells.

DOI：
10.1038/ki.2012.393
发表时间：
2013-05
期刊：
Kidney international
影响因子：
19.6
作者：
通讯作者：

Canonical transient receptor potential 6 (TRPC6), a redox-regulated cation channel.

DOI：
10.1074/jbc.m109.093500
发表时间：
2010-07-23
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Graham S;Ding M;Ding Y;Sours-Brothers S;Luchowski R;Gryczynski Z;Yorio T;Ma H;Ma R
通讯作者：
Ma R

Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.