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 ?g 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.
The Renin-Angiotensin System in Air Pollution-Mediated Exacerbation of Obesity. Project Narrative. 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 involved in metabolic disorder and exacerbation of 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 cardiovascular disease and obesity, the renin-angiotensin system is highly upregulated. This project will attempt to gain further insight through identification of key signaling pathways, in the kidney and adipocytes, involved in air pollution-mediated dysregulation of the renin-angiotensin system, which may provide novel signaling molecules that can serve as targets for treatment and also allow for identification of biomarkers that can be utilized to distinguish those individuals in the population that may have increased susceptibility to the cardiovascular health effects caused by air pollution-exposure.