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，青春期前儿童肥胖已经成为一种流行病和主要的健康问题。 最近的研究表明，儿童肥胖与儿童肾损伤的风险增加有关。 虽然肥胖和II型糖尿病肾病的发展之间的联系是有据可查的， 儿童肥胖的后果作为一个独立的危险因素在没有糖尿病的发展 肾脏疾病受到的关注较少。目前，有几种肥胖动物模型， 肾脏疾病，但这些模型在调查的早期机制，负责有限的使用 高血压、糖尿病和/或青春期之前发生肾损伤。因为大多数肥胖模特 不会发生进行性蛋白尿和慢性肾病（CKD）。最近，我们观察到我们的肥胖大鼠 模型（青春期前肥胖- PPO）发展足细胞损伤和3倍增加蛋白尿之前， 6周龄（儿童期）发生高血压和糖尿病，进展为重度 高血压，CKD，18周龄（成年）。在目前的建议中，我们将使用我们的青春期前模型， 肥胖症，以探讨可能导致肾脏疾病发展的几种机制。拟议 研究将测试肾小球超滤和脂质积聚是否刺激足细胞损伤， 在青春期前肥胖期间，巨噬细胞增殖导致蛋白尿和肾损伤。我们会比较早 PPO模型与对照组之间肾小球毛细血管压（Pgc）的变化， 确定机械应变/周期性拉伸是否对足细胞中的脂质积累有直接影响 分离自两种菌株。我们还将评估巨噬细胞在蛋白尿早期发展中的作用 在PPO模型中。这些结果应该为科学界提供一个肥胖动物模型系统 在青春期前发生蛋白尿，研究肾损伤的机制， 开发新的治疗方法来预防与青春期前儿童相关的肾脏疾病至关重要 肥胖