Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-κB 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 intrarenal 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-κB p65 expression and activity, was involved in the regulation of renal AT₁R expression because GPx1 silencing or treatment with dithiocarbamate (PDTC), an NF-κB 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-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 H₂O₂ production by reducing GPx1 expression, which enhances NF-κB activity, increases renal AT₁R expression, causes sodium retention and consequently increases blood pressure.