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Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule. FASEB J 2023 Apr;37(4):e22835

Date

03/02/2023

Pubmed ID

36856735

Pubmed Central ID

PMC10028530

DOI

10.1096/fj.202200785RR

Scopus ID

2-s2.0-85149427345 (requires institutional sign-in at Scopus site)

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.

Author List

Mukherji ST, Brambilla L, Stuart KB, Mayes I, Kutz LC, Chen Y, Barbosa LA, Elmadbouh I, McDermott JP, Haller ST, Romero MF, Soleimani M, Liu J, Shapiro JI, Blanco GV, Xie Z, Pierre SV

Author

Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Kidney Tubules
Mice
Sodium
Sodium-Hydrogen Exchanger 3
Sodium-Potassium-Exchanging ATPase