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Uncoupling of vasopressin signaling in collecting ducts from rats with CBL-induced liver cirrhosis

¹Department of Pharmacology, University of Copenhagen, DK-2200 Copenhagen N; and ²The Water and Salt Research Center, Institute of Anatomy (Building 233), University of Aarhus, DK-8000 Aarhus C, Denmark

Submitted 7 August 2003 ; accepted in final form 26 May 2004

Vasopressin (AVP) stimulates collecting duct water reabsorption through cAMP-mediated membrane targeting and increased expression of the aquaporin-2 (AQP2) water channel. Rats with liver cirrhosis induced by common bile duct ligation (CBL) show decreased protein expression of AQP2 despite increased plasma concentrations of AVP. The present study was conducted to investigate possible mechanisms behind this uncoupling of AVP signaling. The rats were examined 4 wk after CBL or sham operation. The CBL rats had increased plasma AVP concentrations (CBL: 3.2 ± 0.2 vs. sham: 1.4 ± 0.4 pg/ml, P < 0.05) and reduced AQP2 (0.62 ± 0.11) and phosphorylated AQP2 (0.50 ± 0.06) protein expression compared with sham-operated rats. However, examination of subcellular AQP2 localization by immunohistochemistry showed unchanged plasma membrane targeting in CBL rats, indicating a sustained ability of AQP2 short-term regulation. In a separate series of animals, thirsting was found to normalize AQP2 expression, indicating that AVP uncoupling in CBL rats is a physiological compensatory mechanism aimed at avoiding dilutional hyponatremia. Studies on microdissected collecting ducts from CBL rats showed decreased cAMP accumulation in response to AVP stimulation. The presence of the nonspecific phosphodiesterase inhibitor IBMX normalized the cAMP accumulation, indicating that cAMP-phosphodiesterase activity is increased in CBL rats. However, in contrast to this, Western blotting showed a decreased expression of several phosphodiesterase splice variants. We conclude that CBL rats develop an escape from AVP to prevent the formation of dilutional hyponatremia in response to increased plasma AVP concentrations. The mechanism behind AVP escape seems to involve decreased collecting duct sensitivity to AVP as a result of increased cAMP-phosphodiesterase activity.

aquaporin-2; phosphodiesterase; common bile duct ligation; kidney; cAMP

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