Abstract
The kidney needs to adapt daily to variable dietary K+ contents via various mechanisms including diuretic, acid-base and hormonal changes that are still not fully understood. In this study, we demonstrate that following a K+-deficient diet in wildtype mice, the serine protease CAP2/Tmprss4 is upregulated in connecting tubule and cortical collecting duct and also localizes to the medulla and transitional epithelium of the papilla and minor calyx. Male CAP2/Tmprss4 knockout mice display altered water handling and urine osmolality, enhanced vasopressin response leading to upregulated adenylate cyclase 6 expression and cAMP overproduction, and subsequently greater aquaporin 2 (AQP2) and Na+-K+-2Cl− cotransporter 2 (NKCC2) expression following K+-deficient diet. Urinary acidification coincides with significantly increased H+,K+-ATPase type 2 (HKA2) mRNA and protein expression, and decreased calcium and phosphate excretion. This is accompanied by increased glucocorticoid receptor (GR) protein levels and reduced 11β-hydroxysteroid dehydrogenase 2 activity in knockout mice. Strikingly, genetic nephron-specific deletion of GR leads to the mirrored phenotype of CAP2/Tmprss4 knockouts, including increased water intake and urine output, urinary alkalinisation, downregulation of HKA2, AQP2 and NKCC2. Collectively, our data unveil a novel role of the serine protease CAP2/Tmprss4 and GR on renal water handling upon dietary K+ depletion.
Highlights
Sodium and potassium are essential ions for intra- and extracellular homeostasis
We show that 1) CAP2/Tmprss[4] expression is regulated by dietary K+ intake in specific kidney tubules, and locates in the medulla and the transitional epithelium lining the papilla and minor calyx; 2) CAP2/Tmprss[4] is implicated in renal adaptation to K+ depletion by regulating HKA2, Na+-K+-2Cl− cotransporter 2 (NKCC2) and AQP2; 3) deletion of CAP2/Tmprss[4] is associated with dysregulated glucocorticoid receptor (GR)-mediated signaling, as exemplified by a mirrored phenotype in kidney-specific GR knockout mice
We could detect a significant increase in the mRNA expression of adenylate cyclase 6 (AC6), while the levels of AC5 and the soluble AC were comparable between genotypes (Fig. S3C)
Summary
Sodium and potassium are essential ions for intra- and extracellular homeostasis. The dietary electrolyte content impacts our health[1]; commonly high sodium and low potassium diets lead to high blood pressure and diuretic use[2]. We show that 1) CAP2/Tmprss[4] expression is regulated by dietary K+ intake in specific kidney tubules, and locates in the medulla and the transitional epithelium lining the papilla and minor calyx; 2) CAP2/Tmprss[4] is implicated in renal adaptation to K+ depletion by regulating HKA2, NKCC2 and AQP2; 3) deletion of CAP2/Tmprss[4] is associated with dysregulated GR-mediated signaling, as exemplified by a mirrored phenotype in kidney-specific GR knockout mice. Our results unveil a regulatory function of CAP2/Tmprss[4] and the GR in renal water balance during K+ deprivation These findings may be clinically relevant in conditions resulting in disturbed water handling, as found in nephrogenic diabetes insipidus, Bartter and Gitelman syndromes or in cases of adverse effects following diuretic use. Full-length immunoblots can be found in the supplementary information
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