Aldosterone plays an important role in regulating Na-Cl reabsorption and blood pressure. Epithelial Na+ channel,
Na+-Cl- cotransporter, and
Cl-/HCO3- exchanger pendrin are the major mediators of Na-Cl transport in the
aldosterone-sensitive distal nephron. Existing evidence also suggests that plasma K+ concentration affects renal Na-Cl handling. In this study, we posited that
hypokalemia modulates the effects of
aldosterone on pendrin in
hyperaldosteronism. Chronic
aldosterone infusion in mice increased pendrin levels at the plasma membrane, and correcting
hypokalemia in this model almost completely blocked pendrin upregulation. However,
hypokalemia induced by a low-K+ diet resulted in pendrin downregulation along with reduced plasma
aldosterone levels, indicating that both
hypokalemia and
aldosterone excess are necessary for pendrin induction. In contrast, decreased plasma K+ levels were sufficient to increase
Na+-Cl- cotransporter levels. We found that phosphorylation of
mineralocorticoid receptor that prevents
aldosterone binding in intercalated cells was suppressed by
hypokalemia, which resulted in enhanced pendrin response to
aldosterone, explaining the coordinated action of
aldosterone and
hypokalemia in pendrin regulation. Finally, to address the physiological significance of our observations, we administered
aldosterone to mice lacking pendrin. Notably, plasma K+ levels were significantly lower in pendrin knockout mice (2.7±0.1 mmol/L) than in wild-type mice (3.0±0.1 mmol/L) after
aldosterone infusion, demonstrating that pendrin alleviates
hypokalemia in a state of
aldosterone excess. These data indicate that the decreased plasma K+ levels promote pendrin induction by
aldosterone, which, in concert with
Na+-Cl- cotransporter, counteracts the progression of
hypokalemia but promotes
hypertension in primary
aldosterone excess.