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

ET-1 在 MetS 相关肾小球损伤发生过程中脂质积累中的作用

• 批准号: 9120586
• 负责人: Kasi C McPherson
• 金额: $ 2.59万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2017-08-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120586
• 关键词: Affect; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Central obesity; Chronic; Chronic Kidney Failure; Communities; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dyslipidemias; Endothelin-1; Event; Excretory function; Foam Cells; Goals; Health; High Density Lipoproteins; Hypertension; Hypertriglyceridemia; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Kidney; Kidney Diseases; Knowledge; Link; Lipids; Mechanics; Mediating; Metabolic; Metabolic syndrome; Modeling; Obesity; Paracrine Communication; Patients; Pharmacologic Substance; Population; Prevention; Process; Production; Proteinuria; Rattus; Research; Risk Factors; Rodent Model; Role; Scientist; System; Techniques; Testing; Training Programs; United States; cardiovascular disorder risk; effective therapy; glomerulosclerosis; hemodynamics; in vivo; macrophage; novel; novel therapeutics; oxidized lipid; podocyte; prevent; public health relevance; receptor; research study; skills; treatment strategy

 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.

 描述（由申请人提供）：目前，25%的美国人口患有代谢综合征（MetS），代谢综合征是通过存在以下标准中的至少3种来定义的病症：向心性肥胖、高脂血症、低HDL、糖尿病和高血压。代谢综合征的发病率随肾脏疾病发病率的增加而增加。与代谢综合征相关的肾脏疾病可发生在高血压或糖尿病发作之前。因此，现有的MetS治疗方案在预防或延缓肾脏疾病进展方面仅部分有效。其他研究已经揭示患有慢性肾病（CKD）的肥胖和/或MetS患者存在内皮素-1（ET-1）水平升高。然而，ET-1在与MetS相关的肾脏疾病进展中的作用仍不清楚。由于这些原因，迫切需要确定MetS触发CKD发展的早期机制，以便开发更有效的治疗策略。最近，我们表征了MetS的啮齿动物模型，其发展进行性肾损伤，包括肾脂质积聚，而不发展明显的糖尿病和高血压（SSLepR-/-株）。在当前的提案中，我们将使用该模型来确定这些潜在的机制。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血流动力学的变化，可能有助于在这些大鼠中看到的早期肾损伤。因此，该提议的中心假设是，改变的肾血流动力学是MetS中发生的早期事件，其刺激肾小球ET-1产生，导致通过ETA受体增加足细胞脂质积累，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。我们在三个具体目标中检验中心假设：目的1将研究机械应变的增加是否直接刺激ET-1的产生并有助于足细胞损伤，目的2确定足细胞中脂质积累的增加是由ETA受体介导的，目的3：探讨慢性阻断ET- 1/ET-2受体拮抗剂的作用。ETA级联反应可延缓SSLepR-/-株肾损伤的发展，并防止肾脂质蓄积。该提案将使用新的体内和体外实验技术相结合，以确定ET-1是否参与代谢综合征相关肾脏疾病发展过程中的肾脏脂质蓄积。