(Pro)renin Receptor Regulates LDL-C Metabolism and Exacerbates Atherosclerosis via SREBP2/PCSK9/LDLR Pathway.

BACKGROUND AND OBJECTIVES: The (pro)renin receptor [(P)RR] plays an important role in physiological processes through an angiotensin II (Ang-II) independent pathway. Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease. Its clearance depends on binding to the low-density lipoprotein receptor (LDLR), which is regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) and sterol regulatory elements binding protein 2 (SREBP2). This study aimed to explore whether (P)RR regulates LDL-C metabolism and exacerbated atherosclerosis via an Ang-II independent pathway. METHODS: Apolipoprotein E-knockout mice were fed with a high-fat diet, treated with losartan and received prorenin injection for 8 weeks. Hep G2 cells were incubated with prorenin, small interfering RNA or plasmid for (P)RR, inhibitors of pathway in vitro. In the population study, individuals were divided into two groups based on their plasma renin activity (PRA). Clinical characteristics and LDL-C levels were collected and compared. RESULTS: The mice in the prorenin group exhibited higher liver and plasma levels of LDL-C and a larger aortic plaque area. The (P)RR upregulated the mRNA and protein expression of SREBP2 and PCSK9, while downregulating LDLR expression. Silencing (P)RR or treatment with SREBP2 and/or PCSK9 inhibitor reversed the reduction in LDLR and reduced SREBP2 and PCSK9 expression. Consistent with these findings, participants with higher PRA had significantly higher plasma LDL-C levels in the population study. CONCLUSIONS: (P)RR regulates LDL-C metabolism and promotes atherosclerosis progression via the SREBP2/PCSK9/LDLR pathway. Targeting (P)RR may represent a promising approach to counteract atherosclerosis by lowering LDL-C.