Mechanisms involved in the early development of renal disease associated with prepubertal obesity

与青春期前肥胖相关的肾脏疾病早期发展的机制

• 批准号: 9918350
• 负责人: Jan Michael Williams
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-13 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918350
• 关键词: Adult; Age; Animal Model; Attention; Attenuated; Biological Models; CCL2 gene; Childhood; Childhood Injury; Chronic Kidney Failure; Communities; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease model; Dyslipidemias; Epidemic; Genetic; Glomerular Capillary; Glomerular Filtration Rate; Goals; Health; Hyperglycemia; Hypertension; In Vitro; Infiltration; Injury; Injury to Kidney; Investigation; Kidney; Kidney Diseases; Knock-out; Leptin; Link; Lipids; Mechanics; Mediating; Microalbuminuria; Modeling; Obesity; Operative Surgical Procedures; Pathogenesis; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Prevention; Proteinuria; Puberty; Public Health; Rattus; Renal Blood Flow; Reporting; Risk; Risk Factors; Rodent; Role; Site; Stress; Stretching; Testing; Thinness; Triglycerides; Type 2 diabetic; United States; Up-Regulation; clinically relevant; cytokine; diabetic; glomerular filtration; hemodynamics; in vivo; innovation; leptin receptor; macrophage; mature animal; mutant; novel; obesity development; obesity in children; oxidized low density lipoprotein; podocyte; prepuberty; pressure; prevent; renal damage; salt sensitive; tool; transmission process

Project Abstract Prepubertal childhood obesity has emerged as an epidemic and major health problem in the United States. Recent studies suggest that that childhood obesity is associated with increased risk of renal injury in children. Although the link between obesity and the development of type II diabetic nephropathy is well-documented, the consequences of childhood obesity as an independent risk factor in the absence of diabetes in the development of renal disease has received less attention. Currently, there are several obese animal models that develop renal disease, but these models have limited use in the investigation of the early mechanisms responsible for the development of renal injury prior to hypertension, diabetes, and/or puberty. As most of these obese models do not develop progressive proteinuria and chronic kidney disease (CKD). Recently, we observed our obese rat model (prepubertal obese - PPO) develops podocyte injury and 3-fold increase in proteinuria prior to the development of hypertension and diabetes at 6 weeks of age (childhood), which progresses to severe hypertension, CKD by 18 weeks of age (adulthood). In the current proposal, we will use our model of prepubertal obesity to explore several mechanisms that may contribute to the development of renal disease. The proposed studies will test whether glomerular hyperfiltration and lipid accumulation stimulate podocyte injury and macrophage inflitration leading to proteinuria and renal injury during prepubertal obesity. We will compare early changes in glomerular capillary pressure (Pgc) between the PPO model and their control-lean counterparts and determine whether there is a direct effect of mechanical strain/cyclic stretch on lipid accumulation in podocytes isolated from both strains. We also will evaluate the role of macrophages on the early development of proteinuria in the PPO model. These results should provide the scientific community with an obese animal model system that develops proteinuria, prior to puberty, to study mechanisms involved in renal injury and provide information critical to develop new treatments for the prevention of renal disease associated with prepubertal childhood obesity.

项目摘要 在美国，幼儿肥胖症已经成为流行病和主要健康问题。 最近的研究表明，儿童肥胖与儿童肾脏损伤的风险增加有关。 尽管肥胖与II型糖尿病性肾病的发展之间的联系有据可查，但 在发育中没有糖尿病的情况下，儿童肥胖作为独立危险因素的后果 肾脏疾病的关注较少。目前，有几种肥胖的动物模型 肾脏疾病，但这些模型在调查负责的早期机制方面的使用有限 高血压，糖尿病和/或青春期之前的肾脏损伤发展。作为这些肥胖模型中的大多数 不要发展进行性蛋白尿和慢性肾脏疾病（CKD）。最近，我们观察到肥胖的老鼠 模型（青春期前肥胖-PPO）在蛋白尿之前形成足细胞损伤，蛋白尿增加了3倍 6周龄（儿童）的高血压和糖尿病的发育，这会发展为严重 高血压，CKD到18周龄（成年）。在当前的建议中，我们将使用我们的青春期模型 肥胖以探索可能有助于肾脏疾病发展的几种机制。提议 研究将测试肾小球过滤和脂质积累是否刺激足细胞损伤和 巨噬细胞屈服会导致肥胖前蛋白尿和肾损伤。我们将尽早比较 PPO模型及其对照leean对应物之间的肾小球毛细管压力（PGC）的变化 确定机械应变/环状拉伸对足细胞中脂质积累的直接影响 从两个菌株中分离出来。我们还将评估巨噬细胞在蛋白尿的早期发展中的作用 在PPO模型中。这些结果应为科学界提供肥胖的动物模型系统 这会在青春期之前发展蛋白​​尿，以研究涉及肾脏损伤的机制并提供信息 开发新的治疗方法以预防与青春期前童年相关的肾脏疾病 肥胖。