Identification of miRNAs Mediating Effects of the Renin Angiotensin System in Adipose Tissue (P21-076-19)

Objectives Renin angiotensin system (RAS) classically known to regulate blood pressure, is also involved in several metabolic disorders including obesity. Interestingly, RAS components are highly expressed in adipose tissue; however, mechanisms underlying RAS-obesity interactions are still ambiguous and limited information is available about RAS regulation in adipose tissue. We identified previously that RAS overactivation induces ER stress and inflammation, and our goal is to characterize additional mechanisms linking RAS to obesity. Hence, we hypothesized that overactivation of angiotensinogen (Agt, precursor protein in RAS), modulates processes linked to metabolic diseases such as oxidative stress, apoptosis and autophagy in adipocytes. Methods mRNA and small RNA profiling were performed in adipose tissues of male wild type B6 mice (Wt) and transgenic mice (Agt-Tg) overexpressing Agt which were either fed a low fat (LF) or a high fat (HF) diet with or without RAS inhibitor captopril, an angiotensin converting enzyme inhibitor. Results We identified 18 miRNAs and 5 miRNAs, which were significantly either up or downregulated respectively in Tg compared to Wt mice. Of these, we validated expression of mir195 and 690 which were significantly higher in Tg compared to Wt mice. Furthermore, these miRNAs were significantly reduced in high fat-fed Tg mice treated with captopril compared to non-treated high fat fed mice, indicating the role of angiotensin II in regulation of these miRNAs. Additionally, we identified and validated several genes involved in physiological processes such as oxidative stress and autophagy, some of which were direct targets of the above miRNAs. Mitogen-activated protein kinases including Mapk4, Map3k4, and Map3k7; Caspase 3, 8 and 9; autophagic genes such as autophagy 5 (Atg5), Atg14 and beclin1 were all significantly higher in Tg compared to Wt mice. Additional mechanistic studies are ongoing in cultured adipocytes to further dissect molecular mechanisms linking RAS to obesity. Conclusions Overexpression of RAS in adipose tissue alters various physiological processes such as oxidative stress, apoptosis and autophagy, which could be mediated, in part through regulatory miRNAs. These pathways and miRNAs could be potential therapeutic targets to reduce RAS-associated metabolic diseases. Funding Sources American Heart Association.