Essential role of K_ir5.1 channels in renal salt handling and blood pressure control

Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels K_ir4.1 (Kcnj10) and K_ir5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na⁺ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of K_ir5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SS^{Kcnj16–/–}). SS^{Kcnj16–/–} rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SS^{Kcnj16–/–} rats revealed activity of only homomeric K_ir4.1 channels. K_ir4.1 expression was upregulated in SS^{Kcnj16–/–} rats, but the protein was predominantly localized in the cytosol in SS^{Kcnj16–/–} rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SS^{Kcnj16–/–} rats and prevented or mitigated hypertension in SS^{Kcnj16–/–} or control SS rats, respectively. Our results demonstrate that K_ir5.1 channels are key regulators of renal salt handling in SS hypertension.