ENaC activity in collecting ducts modulates NCC in cirrhotic mice
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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.
KeywordsAscites Aldosterone Cirrhosis Cortical collecting ducts ENaC NCC
We thank Professors A Doucet and B Rossier for constructive comments, Dr. H Mistry, Dr. G Crambert and Dr. N Faller for their helpful reading of the manuscript and discussions and A Tedjani and A Menoud for the technical assistance. We thank Dr. Frederic Schütz (Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics) for his assistance with statistical analysis.
This study was supported by grants from the Swiss National Science Foundation: 31003A_120406 and 31003A_135417 attributed to BV. The laboratory of JL is supported by SNF grant 310030_143929/1.
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