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Kidney-Specific CAP1/Prss8-Deficient Mice Maintain ENaC-Mediated Sodium Balance through an Aldosterone Independent
Elodie Ehret1, Yannick Jäger1,2, Chloé Sergi1
1Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, CH-1011 Lausanne, Switzerland.
International Journal of Molecular Sciences
|June 24, 2022
Summary
Proteolytic activity of prostasin (CAP1/Prss8) is not required for epithelial sodium channel (ENaC) activation. CAP1/Prss8 deficiency uncouples ENaC from aldosterone dependence, maintaining sodium homeostasis via other pathways.
Area of Science:
- Nephrology and Physiology
- Molecular Biology
- Biochemistry
Background:
- Prostasin (CAP1/Prss8) activates the epithelial sodium channel (ENaC).
- The role of CAP1/Prss8's catalytic activity versus its abundance in ENaC activation remains unclear.
- Kidney function relies on precise sodium and potassium handling, regulated by ENaC.
Purpose of the Study:
- To investigate whether CAP1/Prss8's proteolytic activity or its mere presence is essential for ENaC activation in the kidney.
- To elucidate the impact of impaired CAP1/Prss8 function on renal sodium and potassium homeostasis.
- To understand the compensatory mechanisms involved in maintaining sodium balance during CAP1/Prss8 deficiency.
Main Methods:
- Utilized serine 238 mutant (S238A) and renal tubule-specific knockout (Prss8PaxLC1) mice.
- Administered varying sodium (Na+) diets to assess physiological responses.
- Analyzed Na+ and K+ handling, expression of ion transporters, and ENaC subunit cleavage.
- Measured plasma aldosterone, potassium levels, and renin activity.
Main Results:
- CAP1/Prss8 S238A mutants and Prss8PaxLC1 knockout mice showed no significant changes in Na+/K+ handling or ENaC subunit cleavage on standard or low Na+ diets.
- CAP1/Prss8 catalytic activity is dispensable for ENaC activation.
- Prss8PaxLC1 mice exhibited reduced aldosterone and K+ levels but increased plasma renin activity upon Na+ deprivation.
- ENaC activation became uncoupled from aldosterone dependence in CAP1/Prss8-deficient mice.
Conclusions:
- The catalytic activity of prostasin (CAP1/Prss8) is not required for ENaC activation in the kidney.
- CAP1/Prss8 deficiency disrupts the aldosterone-ENaC axis but preserves sodium homeostasis through alternative regulatory pathways.
- These findings highlight the complex regulation of renal sodium balance and the non-proteolytic roles of CAP1/Prss8.
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