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 的团队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通过抑制活性 TGF-b 发挥内源性保护因子的作用。我们发现核心蛋白聚糖确实具有保护作用，因为核心蛋白聚糖敲除小鼠加速了肾脏疾病的发生，并令人惊讶地增加了死亡率。根据我们的结果，AMDCC 研究人员作为一个小组选择了核心蛋白聚糖 KO 糖尿病小鼠作为第一个资助期间的主要成功者。令人感兴趣的是，我们发现死亡的核心蛋白聚糖敲除糖尿病小鼠在死亡前几个月表现出肾功能不全和低血浆脂联素水平的证据。这与人类的临床状况相似。低脂联素水平是肾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，核心蛋白聚糖敲除小鼠肾脏中 NADPH 氧化酶 (Nox4) 的表达增加，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. 脂联素缺乏和核心蛋白聚糖缺乏会导致死亡率增加和糖尿病肾病。 2. 血管平滑肌细胞中 Nox4 的增加会加剧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 小鼠杂交并使用 SM22 启动子产生平滑肌 Nox4 转基因小鼠来产生新的糖尿病小鼠模型。与秋田鼠杂交会诱发糖尿病。这些小鼠将具有糖尿病肾病和心血管疾病的特征。两种新模型都将针对糖尿病肾病进行全面表征。更重要的是，我们提出了一系列介入研究来测试TGF-b、脂联素和Nox4在加速糖尿病肾病发病机制中的因果作用。我们将重点关注的关键特征包括基质积累、肾功能、自动调节和死亡率。拟议的研究与人类状况直接相关，其中 TGF-(、脂联素和 Nox4 是更严重疾病的关键生物标志物，但它们的致病作用尚未得到证实。我们的研究结果将增进我们对糖尿病肾病和血管疾病的机制理解，并可能带来更好的生物标志物和新的治疗方法。