Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule

Abstract

Through its classic ATP-dependent ion-pumping function, basolateral Na/K-ATPase (NKA) generates the Na⁺ gradient that drives apical Na⁺ reabsorption in the renal proximal tubule (RPT), primarily through the Na⁺ /H⁺ exchanger (NHE3). Accordingly, activation of NKA-mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na⁺ reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na⁺ reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na⁺ reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na⁺ /HCO₃ ^- cotransporter (NBCe1A). Urine output and absolute Na⁺ excretion decreased by 65%, driven by increased RPT Na⁺ reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3^-/- mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na⁺ reabsorption by regulating key apical and basolateral Na⁺ transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP-driven function of basolateral Na⁺ reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption.

Keywords: Na/K-ATPase; proximal tubule; salt-sensitive hypertension; signaling; sodium transport.