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Abstract: TH-PO498

Proximal Tubule NBCe1-A-Dependent Regulation of Ammonia and Potassium Metabolism During Hypokalemia

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Lee, Hyun-Wook, University of Florida, Gainesville, Florida, United States
  • Harris, Autumn N., University of Florida, Gainesville, Florida, United States
  • Chen, Chao, University of Florida, Gainesville, Florida, United States
  • Coleman, Richard A., Physiology Dept, U. of MD School of Medicine, Baltimore, Maryland, United States
  • Welling, Paul A., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Romero, Michael F., Mayo Clinic College of Medicine, Rochester, Minnesota, United States
  • Verlander, Jill W., University of Florida, Gainesville, Florida, United States
  • Weiner, I. David, University of Florida, Gainesville, Florida, United States
Background

Dietary potassium restriction is associated with increased ammonia excretion, but neither the specific proteins that signal this response nor the functional role of increased ammonia excretion are known. This study’s purpose was to determine NBCe1-A’s role in the effect of dietary potassium restriction on ammonia metabolism and potassium homeostasis.

Methods

Mice were fed either a K-control diet for 2 days or K-control diet for 2 days followed by K-free diet for 4 days. To determine NBCe1-A’s role we compared mice with NBCe1-A deletion (KO) with wild-type (WT) littermates. All studies included both male and female mice and inclusion of sex in statistical analyses did not change any conclusions.

Results

Urinary ammonia excretion increased during each day of K restriction in WT mice. In KO mice the increase in ammonia excretion was significantly less on each day than in WT mice. Compared to WT, NBCe1-A KO had significantly lower cortical expression of key ammoniagenic proteins, phosphoenolpyruvate carboxykinase and phosphate-dependent glutaminase, and greater expression of the ammonia-recycling protein, glutamine synthetase. NBCe1-A deletion also altered renal K handling during K-free diet. After 4 days of K-free diet, hypokalemia was significantly more severe in KO mice than in WT (KO, 2.5±0.2; WT, 3.5±0.2 mM, P<0.001). Despite more severe hypokalemia, urinary K was significantly greater in KO than WT during dietary potassium restriction. Total NCC and phospho-NCC expression, which decrease renal K excretion, were significantly lower in hypokalemic KO than WT mice. Hypokalemia normally decreases ROMK expression; however, despite more severe hypokalemia in KO mice, ROMK expression did not differ significantly between WT and KO. This suggests abnormal ROMK regulation in NBCe1-A KO mice contributed to the more severe hypokalemia.

Conclusion

1) NBCe1-A is essential to the signaling pathway that increases ammonia excretion in response to dietary potassium restriction; 2) Hypokalemia induced by a K-free diet appears to regulate distal K transport through a proximal tubule-dependent mechanism involving NBCe1-A, signaling through DCT NCC phosphorylation, and regulating ROMK expression.

Funding

  • NIDDK Support