Differential down-regulation of aquaporin-2 in rat kidney zones by peripheral nociceptin/orphanin FQ receptor agonism and vasopressin type-2 receptor antagonism

We previously showed that aquaresis induced by the peripherally acting nociceptin/orphanin FQ receptor agonist ZP120 is associated with a decreased protein level of aquaporin-2 (AQP2) in whole-kidney homogenates. We now examined the effects of Ac-RYYRWKKKKKKK- NH2 (ZP120) (1 nmol/kg/min i.v. for 4 h) on renal regional expression (cortex/outer stripe of outer medulla, inner stripe of outer medulla, and inner medulla) and subcellular localization of aquaporin-2. Responses to ZP120 were compared to the effects of an equi-aquaretic dose (40% inhibition of distal water reabsorption) of the vasopressin type-2 receptor antagonist 5-dimethylamine-1-[4-(2methylbenzoylamino) benzoyl]-2,3,4,5- tetrahydro-1H-benzapine ( OPC31260) ( 32 nmol/ kg/ min). ZP120 decreased the aquaporin- 2 protein level in the rat cortex/ outer stripe of outer medulla and decreased apical plasma membrane localization of aquaporin- 2 in the cortex ( P = 0.002) and in the inner medulla ( P = 0.06). These effects were not accompanied by a decrease in the aquaporin- 2 mRNA level. OPC31260- induced aquaresis was associated with a decreased aquaporin- 2 protein level in both the cortex/ outer stripe of outer medulla and in the inner stripe of outer medulla. Apical localization of aquaporin- 2 was decreased throughout all kidney zones, and OPC31260 decreased the AQP2 mRNA level in the inner medulla. We conclude that equi-aquaretic doses of ZP120 and OPC31260 produce different patterns of aquaporin-2 down-regulation, suggesting different signaling pathways.