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

• 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
• 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

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：空气污染介导的肥胖加重中的肾素-血管紧张素系统。 意义重大。除了对肺部和心血管系统的有害影响外，最近的几个 研究表明，环境空气污染暴露在与以下相关的途径的启动中 心血管疾病的进展，包括代谢紊乱和肥胖，其比率为 目前在全球范围内呈上升趋势。而调节空气污染对新陈代谢影响的途径 综合症和肥胖还没有完全了解，一些研究表明，在心血管疾病和肥胖中， 肾素-血管紧张素系统(RAS)在肾脏和局部脂肪细胞中都高度上调，这是 与新陈代谢和内分泌功能改变有关。阐明系统和组织水平的作用 RAS信号在脂肪细胞功能中可能为未来提供新的途径、生物标志物和/或靶点 治疗方法，还允许在污染暴露的情况下识别易受影响的个人。 创新。我们将分析肾脏、脂肪和组织中RAS的系统和组织水平的调节。 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的血管系统 RAS信号转导及随后脂肪结构和代谢/内分泌功能的改变，包括 脂肪细胞和代谢激素。重要的是，我们将在来自于 C57BL6小鼠，使用与环境相关的暴露浓度，并在高脂和低脂饮食下 条件以及脂肪细胞培养，以努力模拟暴露场景和潜在的 类似于人类群体的病理生理状态。我们将使用miRNA筛选和Multiplex 作为揭示与肥胖有关的代谢/内分泌途径变化的一种方法，以及 免疫荧光和定量聚合酶链式反应确认细胞特异性组织表达和细胞培养提取终点。 明确的目标。我们的初步数据显示，暴露在混合汽油和柴油发动机排放(MVE)中 结果脂肪细胞肥大，全身血管紧张素II(Ang II)升高，肾脏和脂肪增加 高脂饮食对C57BL6小鼠血管紧张素Ⅱ1型受体表达的影响要确定特定的环境- 基因相互作用和信号通路，我们建议调查吸入暴露的假说 MVE导致小鼠肾脏和脂肪细胞中RAS信号的增加，与启动和/或 参与代谢综合征、肥胖和心血管疾病进展的途径恶化。在目标1中，我们将 确定吸入MVE(200MVE g PM/m~3)是否会导致RAS表达改变，miRNA 调节、脂肪细胞结构和/或信号(脂联素、脂肪因子等)。在C57BL6小鼠中处于高水平 与低脂饮食的对比。在目标2中，我们将阐明MVE诱导的循环Ang II在介导血管紧张素转换中的作用。 脂肪细胞的功能和信号，通过ACE抑制剂治疗同时暴露(体内)，以及 我们研究动物的血浆对脂肪细胞培养中局部RAS的shRNA敲除(体外)。