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

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...

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Bibliographic Details
Main Authors: Elodie Ehret, Yannick Jäger, Chloé Sergi, Anne-Marie Mérillat, Thibaud Peyrollaz, Deepika Anand, Qing Wang, Fréderique Ino, Marc Maillard, Stephan Kellenberger, Ivan Gautschi, Roman Szabo, Thomas H. Bugge, Lotte K. Vogel, Edith Hummler, Simona Frateschi
Format: Article
Language:English
Published: MDPI AG 2022-06-01
Series:International Journal of Molecular Sciences
Subjects:
CAP1/Prss8
ENaC activation
Online Access:https://www.mdpi.com/1422-0067/23/12/6745
Description
Summary: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; <i>Prss8<sup>cat/+</sup></i> and <i>Prss8<sup>cat/cat</sup></i>), and renal tubule-specific CAP1/Prss8 knockout (Prss8<sup>PaxLC1</sup>) mice. When exposed to varying Na<sup>+</sup>-containing diets, no changes in Na<sup>+</sup> and K<sup>+</sup> handling and only minor changes in the expression of Na<sup>+</sup> and K<sup>+</sup> 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<sup>+</sup> diet, <i>Prss8<sup>cat/+</sup></i> and <i>Prss8<sup>cat/cat</sup></i> mice exhibited standard plasma aldosterone levels and unchanged amiloride-sensitive rectal potential difference indicating adapted ENaC activity. Upon Na<sup>+</sup> deprivation, mice lacking the renal CAP1/Prss8 expression (Prss8<sup>PaxLC1</sup>) exhibit significantly decreased plasma aldosterone and lower K<sup>+</sup> 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 activation. CAP1/Prss8-deficiency uncoupled ENaC activation from its aldosterone dependence, but Na<sup>+</sup> homeostasis is maintained through alternative pathways.
ISSN:1661-6596
1422-0067

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