(Pro)renin receptor inhibited ABCA1/G1 expression associated with low HDL-c and promoted atherosclerosis

Background

(Pro)renin receptors [(P)RR] binding both renin and its inactive proenzyme for prorenin induce increasing the efficiency of angiotensin I conversion and the production of angiotensin II (Ang II). Recently, (P)RR was reported to played a pathological role in diabetic renal disease independent of Ang II. Ang II is involved in lipid metabolism and atherosclerosis, but the (P)RR participation in atherosclerosis remains unclear. Thus, the objective of this study was to examine the relative importance of Ang II-independent actions of (P)RR and its mechanism in the development of atherosclerosis.

Methods

Clinical demographic characteristics and laboratory profile data of 1189 essential hypertensive were collected. Patients were divided into four groups based on the quartiles of plasma renin activity (PRA). The plasma lipoprotein levels of four groups were compared. Furthermore, we examined serum and liver lipoprotein levels, as well as ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) expression in ApoE ^-/- mice treated with prorenin. ABCA1 and ABCG1 expression and their function in mediating cholesterol efflux were evaluated in THP-1 cells by prorenin treatment. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and liver X receptor α (LXRα) were used to investigate the mechanism involved in vitro.

Results

Plasma TC, TG, LDL-c, and apoB were significantly increased, and HDL-c and apoA were dramatically decreased with a trend of higher plasma renin activity (PRA) ( all P < 0.05) in hypertensive patients. Prorenin accelerated atherosclerosis by inhibiting mRNA and protein expression of ABCA1/ABCG1 in the liver of ApoE ^- / ^- mice. Prorenin binding to (P)RR inhibited the functions of ABCA1- and ABCG1-mediated cholesterol efflux. Furthermore, Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPARγ/LXRα pathway.

Conclusions

(P)RR activated by prorenin inhibited the expression of ABCA1/ABCG1 through the PPARγ/LXRα pathway and the functions of ABCA1- and ABCG1-mediated cholesterol efflux, resulting in dyslipidemia and eventually atherosclerosis.

Highlights

With RPA increases in hypertension, plasma TC, TG, LDL-c, and apoB were higher, while HDL-c and apoA were lower.

Prorenin binding to (P)RR accelerated atherosclerosis by inhibiting ABCA1/G1 expression and function.

Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPARγ/LXRα pathway.