Adiponectin and Nox 4 in Diabetic Kidney Disease

脂联素和 Nox 4 在糖尿病肾病中的作用

• 批准号: 7896015
• 负责人: Kumar Sharma
• 金额: $ 9.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896015
• 关键词: Animal Model; Biological Markers; Blood Vessels; Breeding; Cardiovascular Diseases; Cardiovascular system; Chemicals; Clinical; Core Facility; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; Dose; Exhibits; Funding; Genes; Homeostasis; Human; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Lead; Methods; Modeling; Morbidity - disease rate; Mus; NADPH Oxidase; Nature; Participant; Pathogenesis; Patients; Phase; Phenotype; Plasma; Play; Renal function; Research Personnel; Role; Series; Severities; Smooth Muscle; Smooth Muscle Myocytes; Streptozocin; Testing; Transgenic Mice; Transgenic Organisms; Vascular Diseases; adiponectin; base; clinically relevant; cytokine; decorin; diabetic; in vivo; inhibitor/antagonist; interest; mortality; mouse model; novel; promoter; success

DESCRIPTION (provided by applicant): During the first phase of the AMDCC our group at TJU studied the decorin KO diabetic mouse. Our hypothesis was that decorin acts as an endogenous protective factor by inhibiting active TGF-b. We found that decorin is indeed protective, as decorin KO mice had accelerated kidney disease and surprisingly increased mortality. Based on our results, the AMDCC investigators as a group chose the decorin KO diabetic mouse as a leading success during the 1st funding period. Of major mechanistic interest, we found that decorin KO diabetic mice that died exhibited evidence of renal insufficiency and low plasma adiponectin levels, months prior to mortality. This is similar to the human clinical condition. Low adiponectin levels are a powerful biomarker of increased cardiovascular morbidity and mortality in patients with kidney disease. Additionally, the decorin KO mice had increased NADPH oxidase (Nox4) expression in the kidney which may contribute to more severe nephropathy. In the next phase of the AMDCC, we propose test the following hypotheses. 1. Deficiency of adiponectin in combination with lack of decorin leads to enhanced lethality and diabetic nephropathy and 2. Increased Nox4 in vascular smooth muscle cells enhances diabetic nephropathy and the vascular complications of diabetic kidney disease. We propose to generate new diabetic mouse models by crossing adiponectin KO mice with decorin KO mice and by generating mice transgenic for smooth muscle Nox4 using the SM22 promoter. Diabetes will be induced by crossing with Akita mice. These mice will be characterized for diabetic nephropathy and cardiovascular disease. Both new models will be fully characterized for diabetic nephropathy. More importantly, we propose a series of interventional studies to test the causal role of TGF-b, adiponectin, and Nox4 in the pathogenesis of accelerated diabetic nephropathy. Key features we will focus on include matrix accumulation, renal function, autoregulation, and mortality. The proposed studies are directly related to the human condition, in which TGF-(, adiponectin, and Nox4 are key biomarkers for worse disease, but their pathogenetic role is unproven. Our findings will advance our mechanistic understanding of diabetic nephropathy and vascular disease and may lead to better biomarkers and novel treatments.

描述（由申请人提供）： 在AMDCC的第一阶段，我们在TJU的小组研究了核心蛋白聚糖KO糖尿病小鼠。我们的假设是核心蛋白聚糖作为一种内源性保护因子，通过抑制活性TGF-β。我们发现核心蛋白聚糖确实具有保护作用，因为核心蛋白聚糖基因敲除小鼠的肾脏疾病加速，死亡率惊人地增加。根据我们的结果，AMDCC研究人员作为一个小组选择核心蛋白聚糖KO糖尿病小鼠作为第一个资助期的主要成功。主要机制的兴趣，我们发现，核心蛋白聚糖KO糖尿病小鼠死亡表现出肾功能不全和低血浆脂联素水平的证据，死亡前几个月。这与人类临床状况相似。低脂联素水平是肾脏疾病患者心血管发病率和死亡率增加的有力生物标志物。此外，核心蛋白聚糖KO小鼠肾脏中NADPH氧化酶（Nox 4）表达增加，这可能导致更严重的肾病。在AMDCC的下一阶段，我们建议测试以下假设。1.脂联素缺乏与核心蛋白聚糖缺乏相结合导致死亡率增加和糖尿病肾病;血管平滑肌细胞中Nox 4的增加促进糖尿病肾病和糖尿病肾病的血管并发症我们建议通过将脂联素KO小鼠与核心蛋白聚糖KO小鼠杂交以及通过使用SM 22启动子产生平滑肌Nox 4转基因小鼠来产生新的糖尿病小鼠模型。通过与秋田小鼠杂交诱导糖尿病。将对这些小鼠的糖尿病肾病和心血管疾病进行表征。这两种新模型将充分表征糖尿病肾病。更重要的是，我们提出了一系列的干预性研究，以测试的因果关系的作用，TGF-β，脂联素，和Nox 4在加速糖尿病肾病的发病机制。我们将重点关注的关键特征包括基质蓄积、肾功能、自身调节和死亡率。拟议的研究与人类状况直接相关，其中TGF-β、脂联素和Nox 4是更严重疾病的关键生物标志物，但其致病作用尚未得到证实。我们的发现将促进我们对糖尿病肾病和血管疾病的机制理解，并可能导致更好的生物标志物和新的治疗方法。