Role of FXR in Renal Disease of Metabolic Syndrome and Aging

描述(申请人提供)：肥胖、胰岛素抵抗、糖尿病和衰老是导致肾脏和心血管疾病的主要原因。除了高血压、碳水化合物代谢异常、促纤维化生长因子、促炎细胞因子、氧化应激和晚期糖基化终末产物等重要作用外，脂代谢异常和脂质堆积在肥胖、年龄和糖尿病相关肾脏疾病的发病机制中也起着重要作用。在饮食诱导肥胖和胰岛素抵抗的C57BI/6小鼠以及b)衰老的小鼠和大鼠中，我们发现肾脏核转录因子的表达增加：i)固醇调节元件结合蛋白1和2(SREBP-1和SREBP-2)，以及ii)碳水化合物反应元件结合蛋白(ChREBP)，它导致甘油三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脏硬化和蛋白尿的表现有关。最近的研究表明，法尼类X受体(FXR)通过调节SREBP-1和ChREBP在脂质代谢中发挥重要作用。FXR还具有抗炎和抗肝纤维化的作用。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肥胖和胰岛素抵抗小鼠以及衰老小鼠的肾脏中发生变化。然而，FXR在预防肾脏疾病方面的潜在作用尚不清楚。我们的假设是：1)FXR通过调节肾脏脂肪和碳水化合物代谢、纤维化、炎症和氧化应激，在肾脏疾病的调节中发挥重要作用；2)FXR激动剂的治疗将减轻肥胖和年龄相关性肾脏疾病。我们的目标是：1)确定FXR配体在调节饮食诱导的肥胖和胰岛素抵抗小鼠的a)肾脏疾病、b)肾脏脂质代谢、c)纤维化、d)炎症和e)氧化应激中的作用；2)确定FXR在调节肾小球足细胞对脂肪酸、葡萄糖和胰岛素的反应中的直接作用，包括细胞凋亡、脂代谢、纤维化、炎症和氧化应激；3)确定a)足细胞中FXR的条件性和可诱导性过度表达是否会显著减弱，以及b)足细胞中的FXR基因敲除是否会显著加速肥胖和胰岛素抵抗或年龄相关性肾脏疾病。

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.