Nephropathy in Obesity and Diabetes: Prevention and Treatment

描述（由申请人提供）： 肥胖、胰岛素抵抗和糖尿病是退伍军人以及美国普通人群中肾脏和心血管疾病的主要原因。尽管实施了所有有益的干预措施，但这些患者中的大多数仍发生肾损伤。因此，迫切需要调节肥胖和糖尿病肾病相关致病途径的其他治疗方式。在这个建议中，我们将测试抑制固醇调节元件结合蛋白在预防和治疗 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过表达或肾足细胞特异性SREBP缺失在肥胖和糖尿病肾病中的作用。在具体目标1A中，我们将确定饮食诱导的肥胖和糖尿病在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1 B中，我们将确定饮食诱导的肥胖和糖尿病在a）野生型vs. B）足细胞SREBP敲除小鼠中肾脏疾病发展中的作用。在Specific Aim 1C中，我们将确定SREBP沉默或过表达对人类足细胞对高糖或脂肪酸的反应的直接影响。在具体目标2中，我们将确定SREBP活性抑制在肥胖和糖尿病肾病中的作用。我们将确定SREBP活性的不同抑制剂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;即在糖尿病发作时开始治疗。具体目标2B 我们会进行治疗研究，即是说，一旦有证据显示病人患有肾病，便会开始进行治疗，这样可以更好地模拟临床情况。在特定目标2C中，我们将确定桦木醇、FGH 10019和二甲双胍是否对调节人足细胞对高葡萄糖和脂肪酸的反应具有直接作用，以及这些作用是否通过抑制SREBP特异性介导。影响与创新：SREBP激活的小分子抑制剂在调节肥胖和糖尿病肾病中的肾病中的潜在作用是非常新颖的，并且将对糖尿病和肥胖相关的肾脏和心血管并发症的治疗具有重大的转化意义。该提案的创新方面包括：a）确定最近开发的SREBP活性的小分子抑制剂在肾脏中的作用; B）研究具有肾足细胞特异性敲除或过表达SREBP的小鼠，以确定SREBP在调节肾脂质代谢和肥胖症和糖尿病中的肾脏疾病中的直接肾脏作用。c）确定SREBP过表达或敲除以及SREBP活化的小分子抑制剂在培养的人足细胞中的作用，以确定SREBP在肾细胞中的直接作用，而不依赖于代谢的全身性改变; d）在培养的足细胞中的机制研究，以确定SREBP如何调节足细胞功能和细胞损伤。

DESCRIPTION (provided by applicant): 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.