Role of FXR in Renal Disease of Metabolic Syndrome and Aging

FXR 在代谢综合征和衰老肾脏疾病中的作用

基本信息

批准号：
7541262
负责人：
MOSHE LEVI
金额：
$ 1.68万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7541262
关键词：
ADD-1 protein Advanced Glycosylation End Products Age Aging Agonist Angiotensin II Animal Model Animals Anti-Inflammatory Agents Apoptosis Atherosclerosis Attenuated Binding Proteins Carbohydrates Cardiovascular Diseases Cells Cholesterol Collagen Type IV Development Diabetes Mellitus Diet Disease Dyslipidemias Enzymes Extracellular Matrix Proteins Fatty Acids Fibrates Fibrosis Glucose Growth Growth Factor Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hydroxymethylglutaryl-CoA reductase Hyperglycemia Hypertension Hypertrophy Inflammation Injury Insulin Insulin Resistance Interleukin-6 Kidney Kidney Diseases Knock-out Knockout Mice Ligands Lipids Liver Mediating Metabolic syndrome Mus Nephrosclerosis Nuclear Nuclear Receptors Obesity Oxidative Stress Pathogenesis Plasminogen Activator Inhibitor 1 Play Prevention Prospective Studies Protein Overexpression Proteinuria Rattus Regulation Renal function Research Personnel Response Elements Role Role playing therapy SRE-1 binding protein SRE-2 binding protein SREBP-1a Serum Transforming Growth Factors Transgenic Mice Triglycerides Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vascular Endothelial Growth Factors Work age related base carbohydrate binding protein carbohydrate metabolism carbohydrate receptor cytokine diabetic glomerulosclerosis human TNF protein lipid metabolism non-diabetic podocyte prevent programs receptor receptor expression response saturated fat

项目摘要

Obesity, insulin resistance, diabetes mellitus, and aging are the leading causes of renal andcardiovascular disease. In addition to the important roles played by hypertension, abnormal carbohydrate metabolism, profibrotic growth factors, proinflammatory cytokines, oxidative stress, and advanced glycation end products, abnormal lipid metabolism and accumulation of lipids also play an important role in the pathogenesis of obesity, age, and diabetes-related renal disease. In a) C57BI/6 mice with diet induced obesity and insulin resistance, and b) aging mice and rats, we have found increased renal expression of the nuclear transcriptionalfactors: I) the sterol regulatory element binding proteins 1 and 2 (SREBP-1 and SREBP-2), and II) the carbohydrate response element binding protein (ChREBP), which result in increased synthesis and accumulation of triglyceride and cholesterol and correlate with manifestations of obesity and diabetes related renal sclerosis and proteinuria. Recent studies indicate that the farnesoid X receptor(FXR) plays an important role in lipid metabolism through modulation of SREBP-1 and ChREBP. FXR also has antiinflammatory and antifibrotic effects. FXR is highly expressed in the kidney and we have found that its expression and their target enzymes are altered in the kidneys of mice with diet induced obesity and insulin resistance and in aging mice. However the potential role of FXR in preventing renal disease is not known. Our hypotheses are: 1) FXR plays an important role in regulation of renal disease through modulation of renal lipid and carbohydrate metabolism, fibrosis, inflammation, and oxidative stress; 2) Treatment with FXR agonists will attenuate obesity and age-related renal disease. Our aims are: 1) To determine the role of FXR ligands in modulation of a) renal disease, b) renal lipid metabolism, c) fibrosis, d) inflammation, and e) oxidative stress in I) mice with diet induced obesity and insulin resistance and II) aging mice; 2) To determine the direct role of FXR in modulation of renal glomerular podocyte response to fatty acids, glucose and insulin, including apoptosis, lipid metabolism, fibrosis, inflammation, and oxidative stress;3) To determine if conditional and inducible a) FXR overexpression in podocyteswill significantly attenuate, and alternatively if b) FXR knockout in podocytes will significantly accelerate obesity and insulin resistanceor age-related renal disease.

肥胖，胰岛素抵抗，糖尿病和衰老是肾脏和心脏血管的主要原因疾病。除了高血压发挥的重要作用，异常碳水化合物代谢外，纤维化生长因子，促炎细胞因子，氧化应激和晚期糖基末端产品，异常脂质代谢和脂质的积累也在肥胖，年龄和与糖尿病相关的肾脏疾病的发病机理。在A）饮食诱导的C57BI/6小鼠肥胖和胰岛素抵抗，b）衰老的小鼠和大鼠，我们发现肾脏表达增加核转录因子：i）固醇调节元素结合蛋白1和2（SREBP-1和 SREBP-2）和II）碳水化合物响应元件结合蛋白（CHREBP），这导致增加甘油三酸酯和胆固醇的合成和积累，并与肥胖的表现相关糖尿病相关的肾硬化和蛋白尿。最近的研究表明，Farnesoid X受体（FXR）通过调节SREBP-1和CHREBP，在脂质代谢中起着重要作用。 FXR也有抗炎和抗纤维化作用。 FXR在肾脏中高度表达，我们发现它在饮食诱导的肥胖症和胰岛素的小鼠肾脏中，表达及其靶酶发生了变化抗性和衰老小鼠。但是，未知FXR在预防肾脏疾病中的潜在作用。我们的假设是：1）FXR通过调节而在调节肾脏疾病中起重要作用肾脏脂质和碳水化合物代谢，纤维化，炎症和氧化应激； 2）用FXR治疗激动剂会衰减肥胖症和与年龄相关的肾脏疾病。我们的目标是：1）确定FXR的作用配体调节a）肾脏疾病，b）肾脏脂质代谢，c）纤维化，d）炎症和e）饮食诱导肥胖症和胰岛素抵抗和ii）衰老小鼠的I）小鼠的氧化应激； 2）到确定FXR在调节肾肾小球足细胞对脂肪酸，葡萄糖的直接作用和胰岛素，包括凋亡，脂质代谢，纤维化，炎症和氧化应激； 3）确定有条件的和可诱导的a）podocyteswill中的FXR过表达会显着减弱，并且另外与年龄有关的肾脏疾病。