An altered role of AQP2 water channels in DOCA-salt hypertension was investigated. DOCA-salt hypertension was induced in rats. Control groups were either treated with DOCA alone or subjected to a high-salt intake without DOCA. Four weeks after inducing the hypertension, AQP2 expression and shuttling were determined in the kidney. Adenylate cyclase activity was also determined to examine the upstream affecting the AQP2 system. The AVP-evoked cAMP generation in the cortex and outer medulla was augmented following the treatment with DOCA either alone or combined with high-salt intake. Accordingly, the expression and shuttling of AQP2 proteins were increased in the cortex and outer medulla. These findings suggest that DOCA enhances cAMP generation and expression/shuttling of AQP2 water channels in the kidney, which may be causally related with the development of hypertension.