Dietary K⁺ supplementation restores normal aldosterone level in Na⁺-deprived renal tubule-specific CAP1/Prss8-deficient mice

We previously reported that Na⁺-deprived mice lacking CAP1/Prss8 in kidney tubules maintained epithelial sodium channel-mediated sodium balance albeit persistent hypoaldosteronism, hence indicating an uncoupling from aldosterone production. This further suggested an implication of the serine protease CAP1/Prss8 (prostasin) in the cross talk of the kidney with the adrenal gland that does not express prostasin. When these knockout (Ko) mice were additionally exposed to a high K⁺ diet, plasma K⁺ levels and plasma aldosterone concentrations were normalized and no longer different from those of the control mice. The mRNA transcript expression of the adrenal aldosterone synthase <i>Cyp11b2,</i> which was lower in Na⁺-deprived <i>CAP1/Prss8</i> Ko animals, was in the normal range. Plasma aldosterone levels were similar to control animals, indicating that K⁺ rescued the hypoaldosteronism in Na⁺-deprived <i>CAP1/Prss8</i> Ko animals. These data suggest that CAP1/Prss8 (prostasin) is implicated in the regulation of aldosterone synthesis or production and that the consequences of <i>CAP1/Prss8</i> deficiency can be compensated by high dietary K⁺ supplementation. Prostasin may therefore present a promising regulator of aldosterone production by affecting the adrenal steroidogenic pathway.<b>NEW & NOTEWORTHY</b> We explore the role of the serine protease CAP1/Prss8 in aldosterone synthesis. Described previously as a candidate gene for hypertension, the mechanism by which renal serine protease deficiency is implicated in aldosterone production is still largely unknown. Our findings underscore a role of prostasin in the regulation of aldosterone synthesis. In kidney-specific <i>CAP1/Prss8</i> knockout mice, K⁺ supplementation is predominant over Na⁺ and restores normal aldosterone production proposing new pathways to treat hypo- or hypertension.