The Renin-Angiotensin System in Air Pollution-Mediated Exacerbation of Obesity

空气污染介导的肥胖加剧中的肾素-血管紧张素系统

基本信息

批准号：
9231794
负责人：
Amie Kathleen Lund
金额：
$ 43.8万
依托单位：
UNIVERSITY OF NORTH TEXAS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231794
关键词：
Acute Adipocytes Adipose tissue Air Pollutants Air Pollution Angiotensin II Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Animal Model Animals Atherogenic Diet Atherosclerosis Biological Assay Biological Markers Biological Process Captopril Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cells Cholesterol Chronic Complex Data Deposition Diet Disease Endocrine Energy Metabolism Exposure to Fat-Restricted Diet Fatty acid glycerol esters Fluid Balance Functional disorder Future Gasoline Gene Expression Regulation Glucagon Glucose Growth and Development function High Fat Diet Homeostasis Hormonal Hormone use Hormones Human Hyperlipidemia Hypertrophy Immunofluorescence Immunologic In Vitro Individual Infiltration Inflammation Inhalation Exposure Insulin Insulin Receptor Insulin Resistance Interleukin-6 Kidney Laboratories Leptin Lipids Lipolysis Losartan Lung Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Methodology MicroRNAs Mus Myocardial Infarction Obesity Outcome Pathologic Pathway interactions Peptidyl-Dipeptidase A Plasma Pollution Population Predisposition Prevalence Publishing Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regulation Renin Renin-Angiotensin System Reporting Risk Factors Role SLC2A1 gene Signal Pathway Signal Transduction Signaling Molecule Stroke Structure System Techniques Tissues Type 2 Angiotensin II Receptor Vehicle Emissions Water adipokines adiponectin air filter autocrine biomarker identification cardiovascular health drinking water endothelial dysfunction gene environment interaction glucose receptor in vivo inflammatory marker innovation insight kidney vascular structure knock-down lipid biosynthesis macrophage novel oxidized low density lipoprotein paracrine pollutant receptor expression screening sedentary lifestyle small hairpin RNA steroid metabolism

项目摘要

Project Abstract: The Renin-Angiotensin System in Air Pollution-Mediated Exacerbation of Obesity. Significance. In addition to its harmful effects in the pulmonary and cardiovascular systems, several recent studies have implicated environmental air pollution exposure in initiation of pathways associated with progression of cardiovascular disease (CVD), including metabolic disorder and obesity, rates of which are currently increasing worldwide. While the pathways that mediate the effects of air pollution in metabolic syndrome and obesity are not fully understood, several studies have shown that in both CVD and obesity the renin-angiotensin system (RAS) is highly upregulated both in the kidney and locally in adipocytes, which is associated with altered metabolic and endocrine function. Elucidating the role of systemic and tissue level RAS signaling in adipocyte function may provide novel pathways, biomarkers, and/or targets for future therapies and also allow for identification of susceptible individuals in pollution-exposure scenarios. Innovation. We will analyze systemic and tissue level regulation of the RAS in kidney, adipose, and vasculature to determine whether inhalation exposure to traffic-generated air pollutants results in deregulation of RAS signaling and subsequent alterations in adipose structure and metabolic/endocrine function, including adipocytes and metabolic hormones. Importantly, we will conduct these analyses in tissues derived from C57Bl6 mice, using environmentally relevant exposure concentrations, and under both high and low fat diet conditions, as well as adipocyte cell culture, in an effort simulate exposure scenarios and underlying pathophysiologic states similar to that in the human population. We will use miRNA screening and Multiplex assays as an approach to reveal alterations in metabolic/endocrine pathways involved in obesity, as well as immunofluorescence and qPCR to confirm cell-specific tissue expression and cell culture extract endpoints. Specific Aims. Our preliminary data show exposure to mixed gasoline and diesel engine emissions (MVE) results in adipocyte hypertrophy, elevated systemic angiotensin II (Ang II), and increased renal and adipose expression of Ang II type 1 (AT1) receptor in C57Bl6 mice on a high fat diet. To identify specific environment- gene interactions and signaling pathways, we propose to investigate the hypothesis inhalational exposure to MVE results in increased RAS signaling in the kidneys and adipocytes of mice, associated with initiation and/or exacerbation of pathways involved in metabolic syndrome, obesity, and progression of CVD. In Aim 1 we will determine whether inhalation exposure to MVE (200 μg PM/m3) results in altered RAS expression, miRNA regulation, and adipocyte structure and/or signaling (adiponectin, adipokines, etc.) in C57Bl6 mice on a high vs. low fat diet. In Aim 2, we will elucidate the role of MVE-induced circulating Ang II in mediating alterations in adipocyte function and signaling, through ACE-inhibitor treatment concurrent with exposure (in vivo), and also shRNA knockdown of local RAS (in vitro) in adipocyte cell culture treated with plasma from our study animals.

项目摘要：肾素-血管紧张素系统在空气污染介导的肥胖加剧中的作用。除了对肺和心血管系统的有害影响外，最近还有一些影响。研究表明环境空气污染暴露与相关途径的启动有关心血管疾病（CVD）的进展，包括代谢紊乱和肥胖，其发生率目前，介导空气污染对代谢影响的途径在全球范围内不断增加。综合征和肥胖之间的关系尚不完全清楚，多项研究表明，在 CVD 和肥胖中，肾素-血管紧张素系统（RAS）在肾脏和局部脂肪细胞中高度上调，这是与代谢和内分泌功能改变相关。阐明全身和组织水平的作用。脂肪细胞功能中的 RAS 信号传导可能为未来提供新的途径、生物标志物和/或靶点疗法，还可以识别污染暴露场景中的易感个体。创新。我们将分析 RAS 在肾脏、脂肪和组织水平的调节。脉管系统以确定吸入暴露于交通产生的空气污染物是否会导致放松管制 RAS 信号传导以及随后脂肪结构和代谢/内分泌功能的改变，包括重要的是，我们将在源自脂肪细胞和代谢激素的组织中进行这些分析。 C57Bl6 小鼠，使用环境相关暴露浓度，并在高脂肪和低脂肪饮食下条件以及脂肪细胞培养，以努力模拟暴露场景和潜在的我们将使用 miRNA 筛选和 Multiplex 来进行与人类相似的病理生理状态。检测作为揭示肥胖相关代谢/内分泌途径变化的方法，以及免疫荧光和 qPCR 来确认细胞特异性组织表达和细胞培养提取物终点。具体目标。我们的初步数据显示了汽油和柴油发动机混合排放 (MVE) 的暴露情况。导致脂肪细胞肥大、全身血管紧张素 II (Ang II) 升高以及肾和脂肪细胞增加 Ang II 1 型 (AT1) 受体在高脂肪饮食的 C57Bl6 小鼠中的表达确定特定环境。基因相互作用和信号通路，我们建议研究吸入暴露的假设 MVE 导致小鼠肾脏和脂肪细胞中 RAS 信号传导增加，与启动和/或在目标 1 中，我们将改善与代谢综合征、肥胖和 CVD 进展相关的途径。确定吸入暴露于 MVE (200 μg PM/m3) 是否会导致 RAS 表达、miRNA 改变 C57Bl6 小鼠中高脂血症的调节、脂肪细胞结构和/或信号传导（脂联素、脂肪因子等）与低脂饮食相比，在目标 2 中，我们将阐明 MVE 诱导的循环 Ang II 在介导 Ang II 改变中的作用。通过 ACE 抑制剂治疗与暴露（体内）同时进行的脂肪细胞功能和信号传导，以及在用我们研究动物的血浆处理的脂肪细胞培养物中，shRNA 敲低局部 RAS（体外）。