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Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11-Hydroxysteroid Dehydrogenase in Rats with CCl₄-Induced Decompensated Liver Cirrhosis

Soo Wan Kim^*,, Uffe K. Schou^*, Christian D. Peters^*, Sophie de Seigneux^*, Tae-Hwan Kwon^*,, Mark A. Knepper, Thomas E.N. Jonassen^||, Jørgen Frøki^* and Søren Nielsen^*

^* The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Korea; Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and ^|| Department of Pharmacology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark

Address correspondence to: Dr. Søren Nielsen, The Water and Salt Research Center, Building 233/234, University of Aarhus, Aarhus, Denmark DK-8000. Phone: +45-8942-3046; Fax: +45-8619-8664; sn{at}ana.au.dk

Received for publication August 31, 2004. Accepted for publication August 9, 2005.

It was hypothesized that dysregulation of renal epithelial sodium channel (ENaC) subunits and/or 11-hydroxysteroid dehydrogenase (11HSD2) may play a role in the increased sodium retention in liver cirrhosis (LC). Experimental LC was induced in rats by CCl₄ (1 ml/kg, intraperitoneally, twice a week) for 12 wk (protocol 1) or for 11 wk (protocol 2). In both protocols, one group of rats with cirrhosis showed significantly decreased urinary sodium excretion and urinary Na/K ratio (group A), whereas a second group exhibited normal urinary sodium excretion (group B) compared with controls, even though extensive ascites was seen in both groups of rats with cirrhosis. In group A, protein abundance of -ENaC was unchanged, whereas -ENaC abundance was decreased in the cortex/outer stripe of outer medulla compared with controls. The -ENaC underwent a complex change associated with increased abundance of the 70-kD band with a concomitant decrease in the main 85-kD band, corresponding to an aldosterone effect. In contrast, no changes in the abundance of ENaC subunit were observed in group B. Immunoperoxidase microscopy revealed an increased apical targeting of -, -, and -ENaC subunits in distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical and medullary collecting duct segments in group A but not in group B. Immunolabeling intensity of 11HSD2 in the DCT2, CNT, and cortical collecting duct was significantly reduced in group A but not in group B, and this was confirmed by immunoblotting. In conclusion, increased apical targeting of ENaC subunits combined with diminished abundance of 11HSD2 in the DCT2, CNT, and cortical collecting duct is likely to play a role in the sodium retaining stage of liver cirrhosis.

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