Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance

Abstract

Aldosterone promotes electrogenic sodium reabsorption through the amiloride-sensitive epithelial sodium channel (ENaC). Here, we investigated the importance of ENaC and its positive regulator channel-activating protease 1 (CAP1/Prss8) in colon. Mice lacking the αENaC subunit in colonic superficial cells (Scnn1aKO) were viable, without fetal or perinatal lethality. Control mice fed a regular or low-salt diet had a significantly higher amiloride-sensitive rectal potential difference (ΔPDamil) than control mice fed a high-salt diet. In Scnn1aKO mice, however, this salt restriction-induced increase in ΔPDamil did not occur, and the circadian rhythmof ΔPDamil was blunted. Plasma and urinary sodiumand potassiumdid not change with regular or high-salt diets or potassium loading in control or Scnn1aKO mice. However, Scnn1aKO mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention. Mice lacking the CAP1/Prss8 in colonic superficial cells (Prss8KO) were viable, without fetal or perinatal lethality. Compared with controls, Prss8KO mice fed regular or low-salt diets exhibited significantly reduced ΔPDamil in the afternoon, but the circadian rhythmwasmaintained. Prss8KO mice fed a low-salt diet also exhibited sodium loss through feces and higher plasma aldosterone levels. Thus, we identified CAP1/Prss8 as an in vivo regulator of ENaC in colon. We conclude that, under salt restriction, activation of the renin-angiotensin-aldosterone system in the kidney compensated for the absence of ENaC in colonic surface epithelium, leading to colon-specific pseudohypoaldosteronism type 1 with mineralocorticoid resistance without evidence of impaired potassium balance.