Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance.
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 (Scnn1a(KO)) 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 (∆PDamil) than control mice fed a high-salt diet. In Scnn1a(KO) mice, however, this salt restriction-induced increase in ∆PDamil did not occur, and the circadian rhythm of ∆PDamil was blunted. Plasma and urinary sodium and potassium did not change with regular or high-salt diets or potassium loading in control or Scnn1a(KO) mice. However, Scnn1a(KO) 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 (Prss8(KO)) were viable, without fetal or perinatal lethality. Compared with controls, Prss8(KO) mice fed regular or low-salt diets exhibited significantly reduced ∆PDamil in the afternoon, but the circadian rhythm was maintained. Prss8(KO) 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.
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
Sumedha
S
Malsure
Service of Nephrology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland; and Division of Physiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Qing
Q
Wang
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
Roch-Philippe
RP
Charles
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
Chloe
C
Sergi
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
Romain
R
Perrier
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
Birgitte Mønster
BM
Christensen
Service of Nephrology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland; and.
Marc
M
Maillard
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
Bernard C
BC
Rossier
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; Edith.Hummler@unil.ch.
Edith
E
Hummler
D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D003106:Colon / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000172:deficiency / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D012697:Serine Endopeptidases / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D000099271:Prostasin
D000450:Aldosterone; D053503:Epithelial Sodium Channels; D012697:Serine Endopeptidases; D012964:Sodium; D000099271:Prostasin