Dysregulation of renal aquaporins and Na-Cl cotransporter in CCl4-induced cirrhosis

Autor: Patricia Fernández-Llama, Mark A. Knepper, Søren Nielsen, Marta Bosch-Marcé, Vicente Arroyo, Wladimiro Jiménez
Rok vydání: 2000
Předmět:
Zdroj: Kidney International. 58(1):216-228
ISSN: 0085-2538
DOI: 10.1046/j.1523-1755.2000.00156.x
Popis: Dysregulation of renal aquaporins and Na-Cl cotransporter in Hepatic cirrhosis is associated with defective regula- CCl4-induced cirrhosis. tion of water balance. At initial stages of decompensated Background. Severe hepatic cirrhosis is associated with ab- cirrhosis, water retention by the kidney is initially isos- normal renal water retention. motic and is thought to be secondary to excessive stimu- Methods. Semiquantitative immunoblotting was employed lation of renal tubule salt absorption. At least part of to investigate the abundance of the major renal aquaporins (water channels) and sodium-dependent cotransporters in kid- this isosmotic water retention is thought to be associated neys from control rats and rats with cirrhosis secondary to with a marked increase in proximal tubule fluid absorp- chronic CCl4 inhalation. tion documented by micropuncture studies in animal Results. The cirrhotic rats had ascites and manifested a water models (1, 2) and lithium clearance measurements in excretion defect detected by a standard water-loading test. cirrhotic patients (3, 4). With more severe hepatic cirrho- The abundance of aquaporin-1 (the major aquaporin in the proximal tubule) was increased, an effect markedly accentu- sis, free water retention can occur in excess of NaCl ated in high-density membrane fractions prepared by differen- retention leading to dilution of the extracellular fluid. tial centrifugation. Differential centrifugation studies demon- Excess free water retention presumably involves modu- strated a redistribution of aquaporin-2 from high-density to lation of water transport beyond the proximal tubule. low-density membranes, compatible with increased trafficking Both phases of water retention are reproduced in animal of aquaporin-2 to the plasma membrane. The abundance of aquaporin-3, but not aquaporin-2, was increased in collecting models of hepatic cirrhosis, including a model of cirrhosis ducts of rats with CCl4-induced cirrhosis. The Na-K-2Cl co- induced by repetitive CCl4 inhalation (5). In the present transporter of the thick ascending limb showed no change in study, we use the CCl4-inhalation model of hepatic cir- abundance. However, the abundance of the thiazide-sensitive rhosis to investigate the molecular basis of the water Na-Cl cotransporter of the distal convoluted tubule was mark- excretion abnormalities seen in hepatic cirrhosis. edly suppressed in cirrhotic rats, possibly contributing to a defect in urinary dilution. Physiological studies in aquaporin knockout mice (6, 7) Conclusions. In this model of cirrhosis, the development of and studies of patients with mutations of the aquaporin-2 a defect in urinary dilution may be multifactorial, with contribu- water channel (8) have made it clear that the major tions from at least four abnormalities in transporter regulation: fraction of water transport across renal tubule epithelia (1) an increase in the renal abundance of aquaporin-1, (2 )a is mediated by aquaporins. Thus, the abundance of indi- cellular redistribution of aquaporin-2 in the collecting duct vidual aquaporins in the plasma membranes of renal compatible with trafficking to the plasma membrane without an increase in total cellular aquaporin-2, (3) an increase in the epithelial cells is believed to be the major determinant renal abundance of aquaporin-3, and (4) a decrease in the of epithelial water permeability. Aquaporins are ex- abundance of the thiazide-sensitive cotransporter of the distal pressed in three main sites in the kidney, namely, the convoluted tubule. proximal tubule, the descending limb of Henle's loop, and the collecting duct (9). Aquaporin abundance at these sites can be readily assessed by quantitative immu
Databáze: OpenAIRE
Externí odkaz: