Hyperuricemia induces hypertension through activation of renal epithelial sodium channel (ENaC)

Abstract Objectives The mechanisms leading to hypertension associated with hyperuricemia are still unclear. The activity of the distal nephron epithelial sodium channel (ENaC) is an important determinant of sodium balance and blood pressure. Our aim was to investigate whether the effect of hyperuricemia on blood pressure is related to ENaC activation. Methods A hyperuricemic model was induced in rats by 2% oxonic acid and 6 mg/dl uric acid (UA). The hyperuricemic rats were co-treated with either 10 mg/kg/d benzbromarone (Ben) or 1 mg/kg/d amiloride (Ami). Blood pressure was monitored using a tail-cuff, and blood, urine, and kidney samples were taken. Western blotting and immunohistochemical staining were performed to determine the expressions of ENaC subunits and components of the ENaC Regulatory Complex (ERC) in kidney tissue or mCCD cells. Results Serum uric acid (SUA) was increased 2.5–3.5 times above normal in hyperuricemic rats after 3 weeks and remained at these high levels until 6 weeks. The in vivo rise in SUA was followed by elevated blood pressure, renal tubulointerstitial injury, and increased expressions of ENaC subunits, SGK1, and GILZ1, which were prevented by Ben treatment. The decrease in urinary Na+ excretion in hyperuricemic rats was blunted by Ami. UA induced the expression of all three ENaC subunits, SGK1, and GILZ1, and increased Na+ transport in mCCD cells. Phosphorylation of ERK was significantly decreased in both UA-treated mCCD cells and hyperuricemic rat kidney; this effect was prevented by Ben co-treatment. Conclusion Our findings suggest that elevated serum uric acid could induce hypertension by activation of ENaC and regulation of ERC expression.