Adiponectin and Nox 4 in Diabetic Kidney Disease

描述(由申请人提供)： 在AMDCC的第一阶段，我们在天津大学的团队研究了Decorin KO糖尿病小鼠。我们的假设是核心蛋白聚糖通过抑制活性的转化生长因子-β而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，因为核心蛋白核心蛋白KO小鼠加速了肾脏疾病，并出人意料地增加了死亡率。根据我们的结果，AMDCC的研究人员作为一个整体选择了Decin KO糖尿病小鼠作为第一个资助期的领先成功。主要的机制兴趣是，我们发现Decorin KO糖尿病死亡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。这与人类的临床情况相似。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一个强有力的生物标志物。此外，Decorin KO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，我们建议检验以下假设。1.脂联素缺乏与核心蛋白聚糖缺乏共同导致致死率升高和糖尿病肾病。2.血管平滑肌细胞中NOX4的增加加剧了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Decorin KO小鼠杂交，并使用SM22启动子产生平滑肌NOX4转基因小鼠来建立新的糖尿病小鼠模型。与秋田鼠杂交会诱发糖尿病。这些小鼠将以糖尿病肾病和心血管疾病为特征。这两种新模型都将被完全描述为糖尿病肾病。更重要的是，我们提出了一系列干预性研究，以测试转化生长因子-β、脂联素和NOX4在加速糖尿病肾病发病机制中的因果作用。我们将关注的主要特征包括基质堆积、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，其中转化生长因子-α、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。我们的发现将促进我们对糖尿病肾病和血管疾病的机制的理解，并可能导致更好的生物标记物和新的治疗方法。

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.