Work

Hyperaldosteronism in Mice Lacking the Distal Polybasic Tract of the γ‐Subunit of the Epithelial Sodium Channel During Sodium Restriction

Year: 2026

Type: article

Abstract: ABSTRACT Aims The epithelial sodium channel ENaC consists of the subunits α, β, and γ and is activated at an individual channel level by proteolytic processing. Murine γENaC contains a distal polybasic tract 186 RKRK mediating proteolytic ENaC activation by serine proteases in vitro. The relevance of ENaC activation at this cleavage site for sodium homeostasis in vivo is unknown. Methods Mice were generated carrying a mutation of the distal polybasic tract (RKRK186QQQQ or γENaC ki/ki ) using CRISP/Cas9. Sodium homeostasis and proteolytic processing of γENaC were investigated under a low sodium diet, pharmacological ENaC blockade, and induction of nephrotic syndrome. Results Under control conditions, the response to bolus amiloride was reduced in γENaC ki/ki mice compared to γENaC wt/wt mice. Under a low sodium diet for 4 days, urinary sodium excretion was similarly lowered in both genotypes; however, γENaC ki/ki mice required significantly higher plasma aldosterone concentrations. Both genotypes were similarly tolerant to amiloride exposure for 4 days and developed similar sodium retention and body weight gain after induction of nephrotic syndrome. Proteolytic processing of γENaC leading to increased expression of distally cleaved γENaC at ~54 kDa was stimulated in both γENaC wt/wt and γENaC ki/ki mice under all interventions without an appreciable difference in the migration pattern. Conclusion Mice harboring the RKRK186QQQQ mutation of the distal polybasic tract develop hyperaldosteronism under a low sodium diet, pointing to the relevance of this tract for sodium preservation. However, proteolytical processing of γENaC in these mice appears to be compensated for by the involvement of other adjacent cleavage sites.

Source: Acta Physiologica

DOI: 10.1111/apha.70228