The role of ET-1 in lipid accumulation during the development of glomerular injury associated with MetS

 描述(申请人提供)：目前，25%的美国人口患有代谢综合征(METS)，这是一种至少存在以下三项标准的情况：中心性肥胖、高甘油三酯血症、低高密度脂蛋白、糖尿病和高血压。甲型肝炎的发病率与肾脏疾病的发病率增加是平行的。与甲硫氨酸肾病相关的肾脏疾病可在高血压或糖尿病发作之前发生。因此，可供选择的甲硫氨酸治疗方案在预防或延缓肾脏疾病进展方面仅部分有效。其他研究表明，肥胖和/或患有慢性肾脏疾病(CKD)的METS患者存在内皮素-1(ET-1)水平升高。然而，ET-1在蛋氨酸肾病进展中的作用仍不清楚。出于这些原因，迫切需要确定蛋氨酸引发慢性肾脏病的早期机制，以便开发更有效的治疗策略。最近，我们描述了一种甲硫氨酸的啮齿动物模型，该模型发生进行性肾损伤，包括肾脏脂质堆积，但没有明显的糖尿病和高血压(SSLepR-/-株)。在目前的提案中，我们将使用这一模型来确定这些基本机制。我们的初步数据表明，ET-1的产生与蛋白尿的早期发展和肾脏血流动力学的变化有关，这可能是导致这些大鼠早期肾损伤的原因之一。因此，这一建议的中心假设是，肾脏血流动力学改变是METS的早期事件，刺激肾小球ET-1的产生，导致通过ETA受体增加足细胞脂质积聚，从而促进慢性炎症，导致足细胞损伤、蛋白尿、肾小球硬化和CKD。我们在三个特定的目的中检验中心假设：目的1将调查机械应变的增加是否直接刺激ET-1的产生并促进足细胞损伤，目的2确定足细胞中脂质积累的增加是由ETA受体介导的，以及目的3测试慢性阻断ET-1/ETA级联在延缓肾脏损伤发展和防止SSLepR-/-株的肾脏脂质积累方面的作用。这项建议将使用新的体内和体外实验技术相结合来确定ET-1是否参与了与蛋氨酸相关的肾脏疾病发展过程中的肾脏脂质堆积。

 DESCRIPTION (provided by applicant): Currently, 25% of the U.S population suffers from metabolic syndrome (MetS) which is a condition defined by the presence of at least 3 of these criteria: central obesity, hypertriglyceridemia, low HDL, diabetes and hypertension. The incidence of MetS has paralleled the increasing rate of renal disease. Renal disease associated with MetS can occur before the onset of hypertension or diabetes. Consequently, available treatment options for MetS are only partially effective in preventing or delaying the progression of renal disease. Other studies have revealed obese and/or MetS patients with chronic kidney disease (CKD) present with elevated levels of endothelin-1 (ET-1). However, the role of ET-1 in the progression of renal disease associated with MetS remains unclear. For these reasons, there is a critical need to identify the early mechanisms by which MetS triggers the development of CKD so that more effective treatment strategies can be developed. Recently, we characterized a rodent model of MetS that develops progressive renal injury including renal lipid accumulation without developing overt diabetes and hypertension (SSLepR-/- strain). In the current proposal, we will use this model to determine these underlying mechanisms. Our preliminary data suggest ET-1 production is associated with the early development of proteinuria and changes in renal hemodynamics that may contribute to the early renal injury seen in these rats. Therefore, the central hypothesis of this proposal is that altered renal hemodynamics is an early event occurring in MetS that stimulates glomerular ET-1 production leading to increase podocyte lipid accumulation via the ETA receptor thus facilitating chronic inflammation resulting in podocyte damage, proteinuria, glomerulosclerosis and CKD. We test the central hypothesis in three specific aims: Aim 1 will investigate whether increases in mechanical strain directly stimulates ET-1 production and contributes to podocyte injury, Aim 2 determine that increased lipid accumulation in podocytes is mediated by the ETA receptor, and Aim 3 to test the effects chronic blockade of the ET- 1/ETA cascade in delayig the development of renal injury and prevent renal lipid accumulation in the SSLepR-/- strain. This proposal will use a combination of novel in vivo and in vitro experimental techniques to determine whether ET-1 participates in renal lipid accumulation during the development of renal disease associated with MetS.