Original Article
Kidney International (2000) 58, 216–228; doi:10.1046/j.1523-1755.2000.00156.x
Dysregulation of renal aquaporins and Na-Cl cotransporter in CCl4-induced cirrhosis
Patricia Fernández-Llama, Wladimiro Jimenez, Marta Bosch-Marcé, Vicente Arroyo, Søren Nielsen and Mark A Knepper
Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Hormonal Laboratory, Institut Malalties Digestives, Hospital Clínic Universitari, University of Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, and Instituto Reina Sofia de Investigaciones Nefrológicas, Madrid, Spain; and Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark
Correspondence: Mark A. Knepper, M.D., Ph.D., National Institutes of Health, Building 10, Room 6N260, 10 Center Drive, MSC 1603, Bethesda, Maryland 20892-1603, USA. E-mail: knep@helix.nih.gov
Received 3 August 1999; Revised 11 January 2000; Accepted 2 February 2000.
Abstract
Dysregulation of renal aquaporins and Na-Cl cotransporter in CCl4-induced cirrhosis.
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.
Keywords:
sodium-chloride cotransporter, thiazide, urinary dilution, water channels, hepatic cirrhosis
