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.
Fernández-Llama
P
P
Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1603, USA.
Jimenez
W
W
Bosch-Marcé
M
M
Arroyo
V
V
Nielsen
S
S
Knepper
M A
MA
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
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