title: ENaC activity in collecting ducts modulates NCC in cirrhotic mice.
abstract: Cirrhosis is a frequent and severe disease, complicated by renal sodium retention leading to ascites and oedema. A better understanding of the complex mechanisms responsible for renal sodium handling could improve clinical management of sodium retention. Our aim was to determine the importance of the amiloride-sensitive epithelial sodium channel (ENaC) in collecting ducts in compensate and decompensate cirrhosis. Bile duct ligation was performed in control mice (CTL) and collecting duct-specific αENaC knockout (KO) mice, and ascites development, aldosterone plasma concentration, urinary sodium/potassium ratio and sodium transporter expression were compared. Disruption of ENaC in collecting ducts (CDs) did not alter ascites development, urinary sodium/potassium ratio, plasma aldosterone concentrations or Na,K-ATPase abundance in CCDs. Total αENaC abundance in whole kidney increased in cirrhotic mice of both genotypes and cleaved forms of α and γ ENaC increased only in ascitic mice of both genotypes. The sodium chloride cotransporter (NCC) abundance was lower in non-ascitic KO, compared to non-ascitic CTL, and increased when ascites appeared. In ascitic mice, the lack of αENaC in CDs induced an upregulation of total ENaC and NCC and correlated with the cleavage of ENaC subunits. This revealed compensatory mechanisms which could also take place when treating the patients with diuretics. These compensatory mechanisms should be considered for future development of therapeutic strategies.
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland. david.mordasini@dkf.unibe.ch.|Department of Clinical Research, University of Bern, Bern, Switzerland. david.mordasini@dkf.unibe.ch.
authors.forename: David
authors.initials: D
authors.lastname: Mordasini
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Loffing-Cueni
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Rohrbach
authors.initials: R
authors.lastname: Beatrice
authors.affiliation: Service of Nephrology and Hypertension, CHUV, Rue du Bugnon 17, CH-1005, Lausanne, Switzerland.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Maillard
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, CH-1005, Lausanne, Switzerland.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.affiliation: Service of Nephrology and Hypertension, CHUV, Rue du Bugnon 17, CH-1005, Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Burnier
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Escher
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vogt
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D051379:Mice; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine; D049992:Sodium Chloride Symporters / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels; C507047:Scnn1a protein, mouse; D049992:Sodium Chloride Symporters; D000450:Aldosterone; D012964:Sodium; D011188:Potassium
keywords: Aldosterone; Ascites; Cirrhosis; Cortical collecting ducts; ENaC; NCC