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Abstract: FR-PO586

Aldosterone Activates NCC Through the Resulting Hypokalemia and Chloride-Sensing Mechanism of WNK4

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Chen, Jen-Chi, Tri-Service General Hospital, Taipei City, Taiwan
  • Cheng, Chih-Jen, Tri-Service General Hospital, Taipei City, Taiwan
Background

Aldosterone increases the expression and apical abundance of ENaC via binding to the mineralocorticoid receptor (MR). However, the underlying mechanism of aldosterone-induced NCC activation is still unclear. Earlier studies have shown that a high potassium diet reversed NCC phosphorylation in aldosterone-treated mice, and vice versa for the NCC dephosphorylation in MR knockout mice. We recently demonstrated that hypokalemia reduces intracellular chloride concentration, which releases WNK4 from chloride-mediated inhibition. We hypothesized that hypokalemia resulting from aldosterone activates WNK4 via the chloride-sensing mechanism.

Methods

Aldosterone solution (100 g/kg/day) or vehicle control (5% DMSO in physiological saline) was administered to chloride-insensitive L319F/L321F WNK4 knockin mice and their control littermates using Alzet osmotic pumps. In vivo NCC activity was reflected by the protein abundance of total and phosphorylated NCC and also by thiazide-sensitive urinary sodium excretion rate. Moreover, other plasma and urine biochemistries were compared.

Results

After two-week aldosterone infusion, both wild-type and chloride-insensitive WNK4 knockin (KI) mice developed a similar metabolic alkalosis (HCO3- 25 vs. 25 mM) and hypokalemia (K+ 2.4 vs. 2.6). Compared with wild-type mice, KI mice had higher urine output (2.1 vs. 3.2 ml/day), urinary sodium excretion (144 vs 221 mmol/day), and blood pressure. Of note, aldosterone increased the total and T58-phosphorylated NCC in wild-type mice. However, aldosterone did not further enhance the already high NCC phosphorylation in KI mice.

Conclusion

In sum, our results support the notion that aldosterone enhances NCC activity via the resulting hypokalemia and chloride-sensing mechanism of WNK4. Moreover, chronic aldosterone infusion induces natriuresis, compatible with aldosterone escape phenomenon, probably related to pressure natriuresis or natriuretic peptides.

Funding

  • Government Support - Non-U.S.