Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-KB pathway

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 (AT1R) expression and function that was reflected by the increase in sodium excretion after the intra-renal infusion of the AT1R 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 AT1R 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-KB p65 expression and activity, was involved in the regulation of renal AT1R expression because treatment with dithiocarbamate (PDTC), an NF-KB inhibitor, reversed the up-regulation of AT1R expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of AT1R expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal AT1R expression, Na+-K+-ATPase activity, hydrogen peroxide (H2O2) generation, and the nuclear translocation of NF-KB 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 H2O2 production by reducing GPx1 expression, which enhances NF-KB activity, increases renal AT1R expression, causes sodium retention and consequently increases blood pressure.

Automated summary

Epidemiological studies have shown an association between low body selenium and hypertension, but the causality remains unclear. In this study, rats on a selenium-deficient diet developed hypertension after 16 weeks, with decreased sodium excretion. The hypertension was associated with increased renal expression and function of the angiotensin II type 1 receptor (AT1R). Selenium deficiency also led to oxidative stress and reduced expression of glutathione peroxidase 1 (GPx1). Treatment with antioxidants or GPx1 mimics reversed the hypertension and normalized AT1R expression. The results indicate that long-term selenium deficiency causes hypertension by reducing sodium excretion and increasing AT1R expression through oxidative stress and GPx1 downregulation.