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Kidney Week

Abstract: SA-PO757

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

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Ehret, Elodie, Universite de Lausanne Faculte de biologie et de medecine, Lausanne, Vaud, Switzerland
  • Jäger, Yannick, Universite de Lausanne Faculte de biologie et de medecine, Lausanne, Vaud, Switzerland
  • Ino, Frederique, Universite de Lausanne Faculte de biologie et de medecine, Lausanne, Vaud, Switzerland
  • Maillard, Marc P., Centre hospitalier universitaire vaudois Service de nephrologie et d'hypertension, Lausanne, Vaud, Switzerland
  • Hummler, Edith, Universite de Lausanne Faculte de biologie et de medecine, Lausanne, Vaud, Switzerland
  • Frateschi, Simona, Universite de Lausanne Faculte de biologie et de medecine, Lausanne, Vaud, Switzerland
Background

The channel-activating protease 1 (CAP1/Prss8) is a glycophosphatidylinositol-anchored protein and is part of the membrane bound serine protease family. In vitro studies revealed CAP1/Prss8 as an activator of the epithelial sodium channel (ENaC). This channel, localized in the distal part and the collecting duct of the nephron, is involved in the maintenance of the electrolytic homeostasis by reabsorbing sodium from the lumen towards the blood. Na+ deprivation normally results in a rise of plasma aldosterone thereby increasing ENaC activity. It is hypothesized that ENaC is proteolytically cleaved by channel-activating proteases furin and CAP1/prostasin.

Methods

To test whether CAP1/Prss8 is required for renal ENaC activation, tubular nephron-specific CAP1/prostasin knockout mice (Prss8lox/lox;Pax8-rtTAtg/o;TRE-LC1tg/0) and control mice were exposed to a low Na+ diet. Physiological parameters including urinary Na+ and K+, plasma electrolytes, aldosterone levels and renin activity were measured. ENaC activity was determined by benzamil-induced natriuresis.

Results

Upon Na+ deprivation, no changes in Na+ and K+ was observed in CAP1/Prss8 knockout mice. α- or yENaC subunit cleavage pattern did not differ. Interestingly, although plasma aldosterone concentration was significantly decreased in CAP1/Prss8 knockout mice, ENaC activity was similar between the two groups, suggesting that the production of aldosterone is uncoupled from the renin-angiotensin system in CAP1/Prss8 knockout mice.

Conclusion

In summary, we were able to show that in vivo, CAP1/Prss8 was not required for ENaC proteolytic activation. Our experiments revealed that the lack of CAP1/Prss8 uncoupled ENaC activation from the classical renin-angiotensin-aldosterone stimulation on Na+ restriction. This study reveals a complex regulation of ENaC function including aldosterone-dependent and independent mechanisms.

Funding

  • Government Support – Non-U.S.