Mechanisms of Renal Lipotoxicity and Injury in Obesity and Diabetes

肥胖和糖尿病肾脂毒性和损伤的机制

• 批准号: 7687661
• 负责人: Jesus H. Dominguez
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687661
• 关键词: Abdomen; Accounting; Address; Adherence; Adipocytes; Albumins; Apoptosis; Appearance; Attention; Binding; Blood capillaries; Cells; Clinical; Consumption; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Dyslipidemias; Epidemiologic Studies; Epithelial; Epithelial Cells; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Focal Adhesion Kinase 1; Functional disorder; Glomerular Capillary; Hyperglycemia; Hypertension; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Injury; Insulin Resistance; Intercellular adhesion molecule 1; Interstitial Nephritis; Kidney; Kidney Diseases; Kidney Failure; LOX gene; Lead; Leukocytes; Link; Lipid Peroxides; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediator of activation protein; Metabolic syndrome; Nonesterified Fatty Acids; Obesity; Organ; Paper; Permeability; Phenotype; Play; Population; Progress Reports; Proteinuria; Proximal Kidney Tubules; Publications; Rattus; Relative (related person); Renal Glycosuria; Renal tubule structure; Reporting; Risk Factors; Role; Saturated Fatty Acids; Series; Serum; Side; Source; System; Testing; Toxic effect; Tubular formation; Unsaturated Fatty Acids; Urine; Veterans; Visceral; base; capillary; cell injury; chemokine; cytotoxic; diabetic; diabetic rat; feeding; in vivo; interstitial; macromolecule; mouse model; novel; oxidized lipid; oxidized low density lipoprotein; public health relevance; receptor; response; uptake; urinary

DESCRIPTION (provided by applicant): The insidious consumption of high fat diets can result in the accumulation of unutilized lipid, or visceral adiposity. Current dietary fats contain a large proportion of proinflammatory saturated fatty acids (PSFA), and proinflammatory lipid peroxides, which accumulate in adipocytes and then in other organs, including renal tubules. The ingestion of high fat diets with resulting adiposity, dyslipidemia and diabetes increases serum levels of oxidized low density lipoprotein (oxLDL). Circulating PSFA and oxLDL stimulate expression of LOX-1, a transporter that internalizes oxLDL and PSFA in renal capillaries and tubules. Once internalized, the lipids alter the normal renal endothelial phenotype into a more permeable proinflammatory phenotype. The abnormal permeability of glomerular and peritubular capillaries allows passage of macromolecules. This important clinical transition is recognized as proteinuria and accompanying toxic lipiduria, and it indicates progression to renal failure. We suggest that the now permeable albumin-bound PSFA and lipid peroxides reach and damage tubules from peritubular and luminal sides. We propose to address the role of lipids in nephropathy with the hypothesis: "Oxidized lipid and saturated fatty acids activate the expression of the oxLDL receptor LOX-1, which promotes a tubular proinflammatory phenotype". We will test this hypothesis in vivo on rat and mouse models of obesity-diabetes and in vitro on rat proximal tubule NRK52E cells. We want to study the mechanism of LOX-1 activation (SA1) and the mechanism by which LOX-1 activation evokes the pro-inflammatory and pro-fibrotic phenotype in renal tubules (SA2). The rationale behind our proposal is based on the presumption that the lipid-driven conversion of proximal tubules to a pro-inflammatory state, pro-fibrogenic state, is an important mechanism of renal failure in diabetes and obesity. PUBLIC HEALTH RELEVANCE: We want to study the mechanisms by which surplus lipid damages the kidney and stimulates an inflammatory response. This is one of the major problems in diabetes- obesity that afflicts our veteran's population.

描述（由申请人提供）： 隐秘地摄入高脂肪饮食会导致未利用的脂质积累，或内脏肥胖。目前的膳食脂肪含有大量促炎饱和脂肪酸（PSFA）和促炎脂质过氧化物，它们在脂肪细胞中积累，然后在包括肾小管在内的其他器官中积累。摄入高脂肪饮食导致肥胖、血脂异常和糖尿病，会增加氧化低密度脂蛋白 (oxLDL) 的血清水平。循环中的 PSFA 和 oxLDL 刺激 LOX-1 的表达，LOX-1 是一种转运蛋白，可将 oxLDL 和 PSFA 内化到肾毛细血管和肾小管中。一旦内化，脂质就会将正常的肾内皮表型改变为更具渗透性的促炎表型。肾小球和肾小管周围毛细血管的异常渗透性允许大分子通过。这种重要的临床转变被认为是蛋白尿和伴随的毒性脂尿，它表明进展为肾衰竭。我们认为现在可渗透的白蛋白结合 PSFA 和脂质过氧化物从肾小管周围和管腔侧到达并损伤肾小管。我们提出以下假设来解决脂质在肾病中的作用：“氧化脂质和饱和脂肪酸激活 oxLDL 受体 LOX-1 的表达，从而促进肾小管促炎表型”。我们将在肥胖-糖尿病大鼠和小鼠模型上体内测试这一假设，并在大鼠近曲小管 NRK52E 细胞上测试这一假设。我们想要研究 LOX-1 激活 (SA1) 的机制以及 LOX-1 激活引起肾小管促炎和促纤维化表型的机制 (SA2)。我们的提议背后的基本原理是基于这样的假设：脂质驱动的近端小管向促炎症状态、促纤维化状态的转变是糖尿病和肥胖症肾衰竭的重要机制。 公共卫生相关性： 我们想要研究多余的脂质损害肾脏并刺激炎症反应的机制。这是困扰我们退伍军人的糖尿病肥胖的主要问题之一。