title: Dysregulation of renal aquaporins and Na-Cl cotransporter in CCl4-induced cirrhosis.
abstract: BACKGROUND
  Severe hepatic cirrhosis is associated with abnormal renal water retention.
  
  
  METHODS
  Semiquantitative immunoblotting was employed to investigate the abundance of the major renal aquaporins (water channels) and sodium-dependent cotransporters in kidneys from control rats and rats with cirrhosis secondary to chronic CCl4 inhalation.
  
  
  RESULTS
  The cirrhotic rats had ascites and manifested a water excretion defect detected by a standard water-loading test. The abundance of aquaporin-1 (the major aquaporin in the proximal tubule) was increased, an effect markedly accentuated in high-density membrane fractions prepared by differential centrifugation. Differential centrifugation studies demonstrated a redistribution of aquaporin-2 from high-density to low-density membranes, compatible with increased trafficking of aquaporin-2 to the plasma membrane. The abundance of aquaporin-3, but not aquaporin-2, was increased in collecting ducts of rats with CCl4-induced cirrhosis. The Na-K-2Cl cotransporter of the thick ascending limb showed no change in abundance. However, the abundance of the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule was markedly suppressed in cirrhotic rats, possibly contributing to a defect in urinary dilution.
  
  
  CONCLUSIONS
  In this model of cirrhosis, the development of a defect in urinary dilution may be multifactorial, with contributions from at least four abnormalities in transporter regulation: (1) an increase in the renal abundance of aquaporin-1, (2) a cellular redistribution of aquaporin-2 in the collecting duct compatible with trafficking to the plasma membrane without an increase in total cellular aquaporin-2, (3) an increase in the renal abundance of aquaporin-3, and (4) a decrease in the abundance of the thiazide-sensitive cotransporter of the distal convoluted tubule.
authors.affiliation: Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1603, USA.
authors.forename: P
authors.initials: P
authors.lastname: Fernández-Llama
authors.forename: W
authors.initials: W
authors.lastname: Jimenez
authors.forename: M
authors.initials: M
authors.lastname: Bosch-Marcé
authors.forename: V
authors.initials: V
authors.lastname: Arroyo
authors.forename: S
authors.initials: S
authors.lastname: Nielsen
authors.forename: M A
authors.initials: MA
authors.lastname: Knepper
mesh_terms: D000818:Animals; D051398:Aquaporin 1; D051399:Aquaporin 2; D051400:Aquaporin 3; D051403:Aquaporin 6; D020346:Aquaporins / Q000032:analysis / Q000378:metabolism*; D002251:Carbon Tetrachloride; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D015151:Immunoblotting; D007671:Kidney Concentrating Ability / Q000502:physiology; D007684:Kidney Tubules / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D049992:Sodium Chloride Symporters; D027981:Symporters
chemical_list: C496022:Aqp1 protein, rat; C496025:Aqp2 protein, rat; C496029:Aqp3 protein, rat; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D002352:Carrier Proteins; D002712:Chlorides; D049992:Sodium Chloride Symporters; D027981:Symporters; D051398:Aquaporin 1; D051400:Aquaporin 3; D012964:Sodium; D002251:Carbon Tetrachloride