Kidney‐Specific CAP1/Prss8‐Deficient Mice Maintain ENaC‐Mediated Sodium Balance through an Aldosterone Independent Pathway

The serine protease prostasin (CAP1/Prss8, channel‐activating protease‐1) is a confirmed in vitro and in vivo activator of the epithelial sodium channel ENaC. To test whether proteolytic activity or CAP1/Prss8 abundance itself are required for ENaC activation in the kidney, we studied animals either hetero‐ or homozygous mutant at serine 238 (S238A; Prss8^cat/+ and Prss8^cat/cat), and renal tubule‐specific CAP1/Prss8 knockout (Prss8^PaxLC1) mice. When exposed to varying Na⁺‐contain-ing diets, no changes in Na⁺ and K⁺ handling and only minor changes in the expression of Na⁺ and K⁺ transporting protein were found in both models. Similarly, the α‐ or γENaC subunit cleavage pattern did not differ from control mice. On standard and low Na⁺ diet, Prss8^cat/+ and Prss8^cat/cat mice exhibited standard plasma aldosterone levels and unchanged amiloride‐sensitive rectal potential difference indicating adapted ENaC activity. Upon Na⁺ deprivation, mice lacking the renal CAP1/Prss8 expression (Prss8^PaxLC1) exhibit significantly decreased plasma aldosterone and lower K⁺ levels but compensate by showing significantly higher plasma renin activity. Our data clearly demonstrated that the catalytic activity of CAP1/Prss8 is dispensable for proteolytic ENaC activa-tion. CAP1/Prss8‐deficiency uncoupled ENaC activation from its aldosterone dependence, but Na⁺ homeostasis is maintained through alternative pathways.