Nephropathy in Obesity and Diabetes: Prevention and Treatment

肥胖、胰岛素抵抗和糖尿病是肾脏和心血管疾病的主要原因， 美国人和普通美国人一样。尽管实施了所有有益的干预措施， 大多数患者会出现肾损伤。调节致病性的其他治疗方式 因此，迫切需要肥胖症和糖尿病性肾病的相关途径。在本提案中，我们将 测试抑制固醇调节元件结合蛋白在预防和治疗中的潜在作用 肥胖和糖尿病中的肾脏疾病。 在特定目的1中，我们将确定肾足细胞特异性SREBP的作用 肾足细胞特异性SREBP在肾脏疾病中的过度表达或缺失 肥胖和糖尿病。在具体目标1A中，我们将确定饮食诱导的肥胖的影响， 糖尿病在a）野生型vs. B）足细胞SREBP过表达小鼠中肾脏疾病发展中的作用。在 具体目标1B：我们将确定饮食诱导的肥胖和糖尿病在肾损害发生中的作用。 a）野生型与B）足细胞SREBP敲除小鼠中的疾病。在具体目标1C中，我们将确定直接 SREBP沉默或过表达在人类足细胞对高葡萄糖或脂肪酸的反应中的作用。 在特定目的2中，我们将确定肾脏中SREBP活性抑制的影响 肥胖症和糖尿病中的疾病。我们将确定不同的SREBP抑制剂的影响， 活性1）桦木醇，2）FGH 10019和3）二甲双胍在糖尿病肾病中的作用。在具体目标2A中，我们将 进行预防性研究;即在糖尿病发病时开始治疗。在具体目标2B中， 将进行治疗研究;也就是说，一旦有肾脏疾病的证据， 能更好地模拟临床环境在特定目标2C中，我们将确定桦木醇、FGH 10019和 二甲双胍可直接调节人足细胞对高糖和高脂肪酸的反应 以及这些影响是否通过抑制SREBP特异性介导。 影响和创新：SREBP激活的小分子抑制剂在调节 肥胖和糖尿病中的肾脏疾病肾脏疾病是一种非常新颖的疾病， 用于治疗糖尿病和肥胖相关的肾脏和心血管并发症。的创新方面 该建议包括：a）确定最近开发的SREBP小分子抑制剂的作用 B）研究肾足细胞特异性敲除或过表达SREBP的小鼠， 确定SREBP在调节肾脂质代谢和肾脏疾病中的直接肾脏作用， 肥胖和糖尿病。c）确定SREBP过表达或敲除以及小分子多肽的影响。 SREBP激活的抑制剂，以确定SREBP在人足细胞中的直接作用。 肾细胞不依赖于代谢的全身性改变; d）在培养物中的足细胞中的机制研究， 确定SREBP如何调节足细胞功能和细胞损伤。

Obesity, insulin resistance, and diabetes mellitus are the leading causes of renal and cardiovascular disease in the Veteran as well as in the general US population. In spite of all the beneficial interventions implemented, renal injury progresses in most of these patients. Additional treatment modalities that modulate the pathogenic pathways involved in obesity and diabetic nephropathy are therefore urgently needed. In this proposal we will test the potential role of inhibition of the sterol regulatory element binding proteins in prevention and treatment of kidney disease in obesity and diabetes. IN SPECIFIC AIM 1 WE WILL DETERMINE THE EFFECTS OF RENAL PODOCYTE SPECIFIC SREBP OVEREXPRESSION or RENAL PODOCYTE SPECIFIC SREBP DELETION IN KIDNEY DISEASE IN OBESITY AND DIABETES. In Specific Aim 1A we will determine the effects of diet induced obesity and diabetes in development of renal disease in a) wild type vs. b) podocyte SREBP overexpressing mice. In Specific Aim 1B we will determine the effects of diet induced obesity and diabetes in development of renal disease in a) wild type vs. b) podocyte SREBP knockout mice. In Specific Aim 1C we will determine the direct effects of SREBP silencing or overexpression in response of human podocytes to high glucose or fatty acids. IN SPECIFIC AIM 2 WE WILL DETERMINE THE EFFECTS OF SREBP ACTIVITY INHIBITION IN KIDNEY DISEASE IN OBESITY AND DIABETES. We will determine the effects of dissimilar inhibitors of SREBP activity 1) Betulin, 2) FGH10019, and 3) Metformin in diabetic kidney disease. In Specific Aim 2A we will perform preventive studies; that is treatments will be started at the onset of diabetes. In Specific Aim 2B we will perform treatment studies; that is treatments will be started once there is evidence of kidney disease which will better simulate the clinical setting. In Specific Aim 2C we will determine if Betulin, FGH10019, and Metformin have direct effects to modulate the response of human podocytes to high glucose and fatty acids and if these affects are specifically mediated via inhibition of SREBPs. Impact and Innovation: The potential role of the small molecule inhibitors of SREBP activation in modulating renal disease in obesity and diabetes renal disease is very novel and will have major translational implications for the treatment of diabetes and obesity-related renal and cardiovascular complications. Innovative aspects of this proposal include: a) Determine the effects of recently developed small molecule inhibitors of SREBP activity in the kidney; b) Study mice with kidney podocyte specific knockout or overexpression of SREBPs to determine the direct renal effects of SREBPs in regulation of renal lipid metabolism and kidney disease in obesity and diabetes. c) Determine the effects of SREBP overexpression or knockout and the small molecule inhibitors of SREBP activation in human podocyte cells in culture to determine the direct effects of SREBPs in renal cells independent of systemic alterations in metabolism; d) Mechanistic studies in podocytes in culture to determine how SREBPs modulate podocyte cell function and cell injury.