Angiotensin II Increases Endoplasmic Reticulum Stress in Adipose Tissue and Adipocytes

Kalhara R Menikdiwela,London Allen,Shane Scoggin,Naima Moustaid-Moussa,Latha Ramalingam,Nishan S Kalupahana

doi:10.1038/s41598-019-44834-8

Kalhara R Menikdiwela, London Allen + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-44834-8

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Journal: Scientific Reports	Publication Date: Jun 11, 2019
Citations: 36	License type: open-access

Affiliation: Texas Tech University, University of Peradeniya

Abstract

The Renin Angiotensin System (RAS), a key regulator of blood pressure has been linked to metabolic disorders. We have previously reported that adipose overexpression of angiotensinogen in mice (Agt-Tg) induces obesity, in part mediated by adipose tissue inflammation, through yet unidentified mechanisms. Hence, we hypothesize that adipose tissue enrichment of angiotensinogen leads to activation of inflammatory cascades and endoplasmic reticulum (ER) stress, thereby, contributing to obesity. We used wild type (Wt), Agt-Tg and Agt-knockout (KO) mice along with 3T3-L1 and human adipocytes treated with RAS, ER stress and inflammation inhibitors. ER stress and pro-inflammation markers were significantly higher in Agt-Tg compared to Wt mice and captopril significantly reduced their expression. Furthermore, in vitro treatment with Ang II significantly induced ER stress and inflammation, whereas angiotensin II receptor inhibitor, telmisartan reduced RAS effects. Moreover, miR-30 family had significantly lower expression in Agt-Tg group. MiR-708-5p and -143-3p were upregulated when RAS was overexpressed, and RAS antagonists reduced miR-143-3p and -708-5p in both mouse adipose tissue and adipocytes. Activation of RAS by Ang II treatment, increased inflammation and ER stress in adipocytes mainly via AT1 receptor, possibly mediated by miR-30 family, -708-5p and/or -143-3p. Hence, RAS and mediating microRNAs could be used as potential targets to reduce RAS induced obesity and related comorbid diseases.

Highlights

Dysfunction of endoplasmic reticulum (ER) leads to immature protein accumulation which activates unfolded protein response (UPR) and is associated with pathways that trigger inflammation and obesity[4,5]
We identified that Renin angiotensin system (RAS) activation in adipose tissue as well as in adipocytes treated with angiotensin II (Ang II), induced ER stress and inflammation, and this primarily occurs via the angiotensin type 1 receptor (AT1) receptor
We wanted to understand the effects of adipose-specific RAS over activation, we used adipose tissue from low fat (LF) fed mice where Agt was overexpressed in the adipose tissue (Agt-Tg)

Summary

Introduction

Dysfunction of ER leads to immature protein accumulation which activates unfolded protein response (UPR) and is associated with pathways that trigger inflammation and obesity[4,5]. RAS inhibitors (e.g. captopril; angiotensin converting enzyme; ACE inhibitor) and Agt knockout (KO) reduced levels of pro-inflammatory markers in mice, indicating that adipose tissue RAS plays an important role in obesity[14,16,17,18]. In vivo and in vitro studies conducted in cardiomyocytes have shown that Ang II induces ER stress[19]. These studies confirm that inflammation could be reduced by inhibiting RAS using its antagonists[19,20]. We identified that RAS activation in adipose tissue as well as in adipocytes treated with Ang II, induced ER stress and inflammation, and this primarily occurs via the AT1 receptor. We have identified a few microRNAs (miR30c-3p, -30a-3p, -143-3p and -708-5p) as potential regulators of RAS induced ER stress and inflammation

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