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：
7796790
负责人：
MOSHE LEVI
金额：
$ 29.67万
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/7796790
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 Dyslipidemias Enzymes Extracellular Matrix Proteins Fatty Acids Fibrates Fibrinogen Fibronectins 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 Proteinuria Rattus Regulation Renal function Research Personnel Response Elements Role 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 lipid metabolism non-diabetic overexpression podocyte prevent programs receptor receptor expression response saturated fat

项目摘要

DESCRIPTION (provided by applicant): Obesity, insulin resistance, diabetes mellitus, and aging are the leading causes of renal and cardiovascular 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 transcriptional factors: 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 podocytes will significantly attenuate, and alternatively if b) FXR knockout in podocytes will significantly accelerate obesity and insulin resistance or age-related renal disease.

描述（由申请人提供）：肥胖，胰岛素抵抗，糖尿病和衰老是肾脏和心血管疾病的主要原因。除了高血压，异常碳水化合物代谢，脱纤维化生长因子，促炎细胞因子，氧化应激和晚期糖化最终产物的重要作用外，脂质代谢以及脂质的累积在脂质异常中也起着重要作用。和与糖尿病有关的肾脏疾病。在A）具有饮食诱导肥胖和胰岛素抵抗的C57BI/6小鼠中，b）衰老小鼠和大鼠，我们发现核转录因子的肾脏表达增加：i）固醇调节元素结合蛋白1和2（SREBP-1和2）和SREBP-2）和II）碳水化合物反应元件结合蛋白（CHREBP），这会导致甘油三酸酯和胆固醇的合成和积累增加，并与肥胖和糖尿病相关的肾硬化症和蛋白尿的表现相关。最近的研究表明，Farnesoid X受体（FXR）通过调节SREBP-1和CHREBP在脂质代谢中起重要作用。 FXR还具有抗炎和抗纤维化作用。 FXR在肾脏中高度表达，我们发现其表达及其靶酶在饮食诱导的肥胖症和胰岛素抵抗以及衰老小鼠的小鼠的肾脏中发生了改变。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通过调节肾脏脂质和碳水化合物代谢，纤维化，炎症和氧化应激而在调节肾脏疾病中起重要作用； 2）用FXR激动剂治疗会减弱肥胖症和与年龄相关的肾脏疾病。我们的目的是：1）确定FXR配体在调节a）肾脏疾病的调节中的作用抗性和II）老化小鼠； 2）确定FXR在调节肾脏肾小球足细胞对脂肪酸，葡萄糖和胰岛素的调节中的直接作用，包括凋亡，脂质代谢，纤维化代谢，纤维化，炎症和氧化应激； 3）确定是否有条件和诱导a）是否有条件a）fxr a）fxr effxr equallexpersectression a）在足细胞中，在足细胞中会大大减弱，如果b）足细胞中的FXR敲除，足以显着加速肥胖和胰岛素抵抗或与年龄相关的肾脏疾病。