Retinol-Binding Protein 4 Actives Adipocyte Renin–Angiotensin System via Toll-Like Receptor 4

Abstract

Abstract Background To investigate the relationship between the levels of serum adipokine retinol-binding protein 4 (RBP4) levels and essential hypertension as well as to explore the role and mechanism of RBP4-induced activation of renin–angiotensin system (RAS) in hypertension in adipocyte. Methods From December 2016 to March 2019, 96 hypertensive patients without treatment and 64 healthy nonhypertensive subjects were recruited. The difference in serum RBP4 levels between the 2 groups was compared, and the relationship between serum RBP4 and hypertension was analyzed by multivariate logistic regression. In mouse primary white adipocytes, the effect and mechanism of RBP4 on RAS in adipocyte were determined by experiment of adenovirus transfected RBP4 overexpression. Protein expression of Toll-like receptor 4 (TLR4) and RAS key components was determined by western blotting. The level of angiotensin II (Ang II) in cell supernatant was measured by enzyme-linked immunosorbent assay. We also observed the effect of TLR4 inhibitor TAK242 on RAS activation induced by RBP4 overexpression. Results Serum RBP4 levels were significantly higher in patients with essential hypertension than in healthy nonhypertensive subjects [30.14 (23.76–40.65) vs. 25.05 (20.05–31.04) µg/ml, P < 0.01]. Multivariate logistic regression analysis showed that RBP4 was independently associated with hypertension [OR 1.10 (95% CI 1.06–1.14), P = 0.002]. In RBP4-transfected adipocytes, the expression of angiotensin-converting enzyme, angiotensinogen, renin/angiotensin-forming enzyme 1, and angiotensin II receptor 1, as well as the level of Ang II in cell supernatant (P < 0.05) were significantly increased. Whereas, activation of RAS system was markedly reduced when RBP4-transfected adipocyte was treated by TAK242 (P < 0.05). Conclusions Serum RBP4 is associated with hypertension. TLR4-mediated activation of RAS might be mechanisms underlying the effects of RBP4 on blood pressure.