Effects of (Pro)renin Receptor on Diabetic Cardiomyopathy Pathological Processes in Rats via the PRR-AMPK-YAP Pathway.

Jie Xiong,Qing Su,Shiran Yu,Bo Dong,Xuefei Dong,Shengnan Li,Jing Chen,Fan Jiang

doi:10.3389/fphys.2021.657378

Abstract

Diabetic cardiomyopathy (DCM) is a common complication associated with diabetes. The (pro)renin receptor (PRR) is an important member of the local tissue renin-angiotensin system and plays a vital role in many cardiovascular diseases. Yes-associated protein (YAP) also plays a crucial role in many cardiovascular diseases. However, the mechanism responsible for the effects of PRR and YAP on DCM remains unclear. The purpose of this study was to determine the role of PRR in the pathological progression of DCM and whether PRR influences the pathological processes of diabetic cardiomyopathy through YAP. We first established diabetic cardiomyopathy rats model, downregulated the expression of PRR, and upregulated and downregulated the expression of YAP. The levels of myocardial inflammation and fibrosis were then measured and cardiac function was evaluated. In vitro, primary rat cardiac fibroblasts (CFs) were cultured with high glucose, with or without transfection with recombinant adenovirus expressing PRR, and GSK621 was used to observe the effect of AMPK. The levels of inflammation and fibrosis were measured in vitro. The results showed that PRR and YAP silencing alleviated myocardial inflammation and fibrosis. GSK621 blocked the effect of PRR on AMPK and YAP and improved CF inflammation and fibrosis. The inhibition of PRR expression offers a new therapeutic strategy for the treatment of DCM. The effects of PRR on the pathological process of DCM in rats may be mediated via the PRR-AMPK-YAP pathway.

Highlights

Diabetic cardiomyopathy (DCM) is a common complication associated with diabetes
The immunohistochemical staining results showed that Yesassociated protein (YAP) protein expression in the DCM group was significantly upregulated compared to that in the control group; this upregulation was significantly alleviated in the Ad-pro(renin) receptor (PRR)-Short hairpin RNA (shRNA) group (Figures 1A–D p < 0.05)
The western blot results showed that the phosphorylation of AMPactivated protein kinase (AMPK) was decreased in the DCM group compared with the control group, and PRR gene silencing increased pAMPK expression in the adenoviruses expressing PRR (Ad-PRR)-shRNA group (Figures 1E,H p < 0.05)

Summary

Introduction

Diabetic cardiomyopathy (DCM) is a common complication associated with diabetes. Due to its insidious onset, rapid development and poor prognosis, it has attracted increasing amounts of attention (Tan et al, 2019). The abnormal proliferation of cardiac fibroblasts and the deposition of extracellular matrix (ECM) aggravate the pathological process (Pro)renin Receptor on Diabetic Cardiomyopathy of cardiac fibrosis, thereby affecting cardiac function (Tao et al, 2019; Arow et al, 2020). There are many studies on the development of diabetic cardiomyopathy, the underlying pathological mechanism of diabetic cardiomyopathy is still not clear. The activity of PRR emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system (RAS). The role of PRR independent of the RAS has received increasing attention in recent years. We suspected that PRR may play an important role in the pathogenesis of diabetic cardiomyopathy

Objectives

Methods

Results

Conclusion