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Abstract: PO2138

Tonic Inhibition of Sodium Reabsorption by Na+/K+-ATPase in the Renal Proximal Tubule

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Mukherji, Shreya T., Marshall Institute for Interdisciplinary Research, Huntington, West Virginia, United States
  • Brambilla, Luca, Marshall Institute for Interdisciplinary Research, Huntington, West Virginia, United States
  • Mayes, Isabella, Marshall Institute for Interdisciplinary Research, Huntington, West Virginia, United States
  • Kutz, Laura C., Marshall Institute for Interdisciplinary Research, Huntington, West Virginia, United States
  • Mcdermott, Jeff P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Haller, Steven T., University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
  • Romero, Michael F., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Liu, Jiang, Joan C Edwards School of Medicine at Marshall University, Huntington, West Virginia, United States
  • Shapiro, Joseph I., Joan C Edwards School of Medicine at Marshall University, Huntington, West Virginia, United States
  • Blanco, Gustavo, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Xie, Zi-jian, Marshall Institute for Interdisciplinary Research, Huntington, West Virginia, United States
  • Pierre, Sandrine V., Marshall Institute for Interdisciplinary Research, Huntington, West Virginia, United States
Background

In the renal proximal tubule (PT), Na+/K+-ATPase (NKA) is exclusively located in the basolateral domain. Through its classic ATP-dependent ion-pumping function, NKA generates the Na+ gradient that drives apical Na+ reabsorption, mostly through Na+/H+ exchanger (NHE3). Accordingly, activation of NKA-mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical Na+ reabsorption (NHE3). In contrast, activation of the more recently discovered NKA signaling triggers a cellular redistribution of PT NKA and NHE3 that decreases Na+ reabsorption.

Methods

We used an in vitro and in vivo gene targeting approach to explicitly test the respective contributions of NKA signaling and ion-pumping in the control of PT Na+ reabsorption.

Results

Knockdown of 90% of NKA in PT LLC-PK1 cells activated NHE3 (50% decrease in inhibitory phosphorylation), and increased basolateral Na+/HCO3- cotransporter (NBCe1A) content. Rescue with wild-type but not Src signaling-null NKA restored NHE3 and NBCe1A to basal levels. In a hypomorphic PT NKA-/- mouse obtained by SGLT2-Cre/LoxP recombination, 70% decrease in PT NKA expression decreased inhibitory phosphorylation of NHE3 and increased membrane abundance of NHE3 and NBCe1A. Urine output and absolute Na+ excretion were decreased by 65%, without histological or functional evidence of renal injury. Those changes were driven by increased PT Na+ reabsorption, as indicated by a 65% decrease in lithium clearance and unchanged GFR. The hyper-reabsorptive phenotype of PT NKA-/- mice were rescued upon crossing with PT NHE3-/- mice, confirming the importance of NKA/NHE3 coupling.

Conclusion

Hence, NKA signaling exerts a tonic inhibition on Na+ reabsorption by regulating key apical and basolateral Na+ transporters. This action, which is lifted upon NKA genetic suppression in cells and in vivo, tonically counteracts NKA’s ATP-driven function of basolateral Na+ reabsorption. Strikingly, NKA/Src signaling is not only physiologically relevant, it is functionally dominant over NKA ion-pumping in the control of PT reabsorption. NKA signaling therefore provides a long sought-after mechanism for the natriuretic action of endogenous NKA ligands such as cardiotonic steroids.

Funding

  • Private Foundation Support