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Abstract: PO1085

Kidney-Specific WNK1 Amplifies NCC Responsiveness to Potassium Imbalance

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Boyd-Shiwarski, Cary R., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Beacham, Rebecca T., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Griffiths, Shawn E., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Shiwarski, Daniel J., Carnegie Mellon University, Pittsburgh, Pennsylvania, United States
  • Knoell, Sophia, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Querry, Katherine E., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Stocker, Sean D., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Subramanya, Arohan R., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
Background

The distal convoluted tubule (DCT) NaCl cotransporter NCC is activated by phosphorylation, a process that is potassium (K+)-regulated and dependent on With-No-Lysine (WNK) kinases. KS-WNK1, a kidney-specific WNK1 isoform lacking the kinase domain, controls WNK signaling pathway localization in the DCT. Its role in NCC regulation, however, is unresolved: while early studies proposed that KS-WNK1 functions as an NCC inhibitor, recent work suggests that it activates NCC.

Methods

To evaluate the role of KS-WNK1 on K+-dependent NCC regulation, we studied KS-WNK1-/- mice across a wide range of plasma K+ (2.0-9.0 mmol/L), induced by dietary maneuvers and diuretic challenges.

Results

K+-restricted KS-WNK1-/- mice exhibited blunted NCC phosphorylation compared to littermates, indicating that KS-WNK1 activates NCC during K+ deficiency. In contrast, NCC phosphorylation was augmented in K+-loaded KS-WNK1-/- mice relative to controls, consistent with KS-WNK1-mediating NCC inhibition during hyperkalemia. Focusing on K+-restricted mice: 1) KS-WNK1-/- mice had mislocalized WNK-SPAK proteins, 2) KS-WNK1-/- mice had blunted activation of the WNK-SPAK/OSR1 kinase cascade, 3) KS-WNK1-/- mice had sex-specific alterations to K+ and Ca2+ plasma levels, 4) KS-WNK1-/- mice had no change to blood pressure, but were less sensitive to thiazide diuretics compared to littermates.

Conclusion

KS-WNK1 has a bimodal effect on NCC, activating NCC during K+ restriction and inhibiting NCC during high K+, thus expanding the inverse relationship between NCC phosphorylation and plasma [K+]. During K+ deprivation, KS-WNK1 facilities the localization and activation of the WNK-SPAK/OSR1 pathway. Mice that lack KS-WNK1 have sex-specific differences in electrolytes, as well as thiazide resistance. These observations clarify the role of KS-WNK1 on NCC, and identify a novel mechanism that contributes to sexual dimorphism in the mammalian nephron.

Funding

  • NIDDK Support