Nephropathy in Obesity and Diabetes: Prevention and Treatment

肥胖和糖尿病引起的肾病：预防和治疗

• 批准号: 8633925
• 负责人: MOSHE LEVI
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633925
• 关键词: ADD-1 protein; Affect; Binding Proteins; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Cholesterol; Clinical; Development; Diabetes Mellitus; Diabetes prevention; Diabetic Nephropathy; Diet; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Generations; Genes; Glucose; Human; Inflammation; Injury; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Laboratories; Lipids; Mediating; Metabolism; Metformin; Mineralocorticoid Receptor; Modality; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Play; Population; Prevention; Preventive; Protein Inhibition; Protein Overexpression; Proteinuria; Proteolysis; Receptor, Angiotensin, Type 1; Regulation; Regulatory Element; Renal function; Role; SRE-1 binding protein; SRE-2 binding protein; Simulate; Sterols; Stress; Testing; Transgenic Organisms; Triglycerides; Veterans; Work; blood glucose regulation; blood pressure regulation; cell injury; genetic regulatory protein; inhibitor/antagonist; innovation; kidney cell; lipid metabolism; mouse model; novel; overexpression; podocyte; prevent; protein activation; public health relevance; response; small molecule

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.

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 退伍军人以及美国一般人口。尽管实施了所有有益的干预措施，但 大多数这些患者的肾脏损伤都在进行。调节致病性的其他治疗方式 因此，迫切需要参与肥胖和糖尿病肾病的途径。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中的潜在作用 肥胖和糖尿病中的肾脏疾病。 在特定目标1中，我们将确定肾脏足细胞特异性SREBP的影响 肾脏疾病中的过表达或肾足细胞特异性SREBP缺失 肥胖和糖尿病。在特定的目标1a中，我们将确定饮食诱发的肥胖和 A）野生型与B）足细胞SREBP过表达小鼠的肾脏疾病发育的糖尿病。在 具体目的1b我们将确定饮食诱导的肥胖和糖尿病在肾脏发展中的影响 a）野生型与b）足细胞SREBP敲除小鼠的疾病。在特定的目标1C中，我们将确定直接 SREBP沉默或过表达对人足细胞对高葡萄糖或脂肪酸的反应的影响。 在特定目标2中，我们将确定肾脏抑制SREBP活性的影响 肥胖和糖尿病中的疾病。我们将确定SREBP不同抑制剂的影响 活性1）Betulin，2）FGH10019和3）二甲双胍在糖尿病肾脏疾病中。在特定的目标2a中，我们将 进行预防研究；这就是治疗方法将在糖尿病开始时开始。在特定的目标2B中 将进行治疗研究；一旦有肾脏疾病的证据，就会开始治疗 将更好地模拟临床环境。在特定的目标2C中，我们将确定Betulin，FGH10019和 二甲双胍具有调节人足细胞对高葡萄糖和脂肪酸的反应的直接作用 如果这些影响是通过抑制SREBP专门介导的。 影响与创新：SREBP激活小分子抑制剂在调节中的潜在作用 肥胖症和糖尿病肾脏疾病的肾脏疾病非常新颖，将具有重大的翻译意义 用于治疗糖尿病和肥胖相关的肾脏和心血管并发症。创新方面 该建议包括：a）确定最近发育的小分子抑制剂的影响 肾脏的活动； b）用肾脏足细胞特异性敲除或SREBPS过表达的小鼠 确定SREBP在调节肾脏脂质代谢和肾脏疾病中的直接肾作用 肥胖和糖尿病。 c）确定SREBP过表达或敲除和小分子的影响 培养物中人口足细胞中SREBP激活的抑制剂，以确定SREBP的直接影响 肾细胞独立于代谢的全身改变； d）在培养的足细胞中的机械研究 确定SREBPS如何调节足细胞功能和细胞损伤。