Selenium deficiency causes hypertension by increasing renal AT receptor expression via GPx1/HO/NF-κB pathway
Free radical biology & medicine
Angiotensin II type 1 receptor; Hypertension; Kidney; Oxidative stress; Selenium deficiency
Epidemiological studies show an association between low body selenium and the risk of hypertension. However, whether selenium deficiency causes hypertension remains unknown. Here, we report that Sprague-Dawley rats fed a selenium-deficient diet for 16 weeks developed hypertension, accompanied with decreased sodium excretion. The hypertension of selenium-deficient rats was associated with increased renal angiotensin II type 1 receptor (ATR) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the ATR antagonist candesartan. Selenium-deficient rats had increased systemic and renal oxidative stress; treatment with the antioxidant tempol for 4 weeks decreased the elevated blood pressure, increased sodium excretion, and normalized renal ATR expression. Among the altered selenoproteins in selenium-deficient rats, the decrease in renal glutathione peroxidase 1 (GPx1) expression was most prominent. GPx1, via regulation of NF-κB p65 expression and activity, was involved in the regulation of renal ATR expression because treatment with dithiocarbamate (PDTC), an NF-κB inhibitor, reversed the up-regulation of ATR expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of ATR expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal ATR expression, Na-K-ATPase activity, hydrogen peroxide (HO) generation, and the nuclear translocation of NF-κB p65 protein in selenium-deficient RPT cells. Our results demonstrated that long-term selenium deficiency causes hypertension, which is due, at least in part, to decreased urine sodium excretion. Selenium deficiency increases HO production by reducing GPx1 expression, which enhances NF-κB activity, increases renal ATR expression, causes sodium retention and consequently increases blood pressure.
Lei, Lifu; Zhang, Fuwei; Huang, Juan; Yang, Xinyue; Zhou, Xiaoxin; Yan, Hongjia; Chen, Caiyu; Zheng, Shuo; Si, Liangyi; Jose, Pedro A.; Zeng, Chunyu; and Yang, Jian, "Selenium deficiency causes hypertension by increasing renal AT receptor expression via GPx1/HO/NF-κB pathway" (2023). GW Authored Works. Paper 2996.