Differential Down-Regulation of Aquaporin-2 in Rat Kidney Zones by Peripheral Nociceptin/Orphanin FQ Receptor Agonism and Vasopressin Type-2 Receptor Antagonism

Abstract

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-NH 2 (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 (ϳ40% inhibition of distal water reabsorption) of the vasopressin type-2 receptor antagonist 5-dimethylamine-1-[4-(2-methylbenzoylamino)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 ϭ 0.002) and in the inner medulla (P ϭ 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.During normal conditions the kidneys regulate renal water excretion to compensate for variations in water intake and extrarenal water loss. The key hormone for regulation of renal water excretion is arginine-vasopressin (AVP), which is released from the posterior pituitary gland in response to an increase in plasma osmolality or a decrease in intravascular volume. AVP regulates water permeability of renal collecting duct (CD) principal cells by both short-and long-term regulation via the G s -coupled AVP type-2 receptor (V 2 -receptor) (Nielsen et al., 1995;Marples et al., 1999). On short term, CD water permeability is increased through cAMP-mediated protein kinase A serine-256 phosphorylation of aquaporin-2 (AQP2), inducing trafficking from intracellular vesicles to the apical membrane (Deen et al., 2000). On long term, protein kinase A phosphorylates and activates the cAMP-responsive element-binding protein to increase AQP2 gene expression (Yasui et al., 1997).In response to a decrease in plasma osmolality or an increase in intravascular volume, water excretion is normally increased through a decreased AVP plasma concentration

GATA2 Regulates Body Water Homeostasis through Maintaining Aquaporin 2 Expression in Renal Collecting Ducts

“…Avpr2-mediated regulation of Aqp2 abundance appears to take place predominantly in the outer medulla and cortical collecting ducts, which are largely impermeable to water in the absence of Avp (43). Indeed, Avpr2 antagonist represses the Aqp2 expression level more predominantly in the outer medulla collecting duct cells than in the inner medulla collecting duct cells (44). Assuming that the Avpr2mediated regulation of Aqp2 abundance is also under the influence of GATA2, the profound reduction of Aqp2 in the outer medulla of Gata2-CKO mice may potentially be due to the diminished Avpr2 expression in the Gata2 CKO mice.…”

Impaired free water excretion in child C cirrhosis and ascites: relations to distal tubular function and the vasopressin system

“…The modulation of AQP2 expression and water retention seems to be mediated partly, but not solely, via V2 receptors. AVP‐independent mechanisms have been shown in several animal studies to play a significant role in modulating collecting duct function and AQP2 expression, which may also be the case in human cirrhosis (28–30, 44, 45).…”

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

“…The NOP partial agonist SER100 has been designed and tested in preclinical studies as an aquaretic. 26,27 The compound also elicits hypotensive and vasorelaxant actions that are more pronounced in spontaneously hypertensive rats. 28 SER100 displayed an acceptable safety profile in patients with isolated systolic hypertension and produced significant lowering of systolic blood pressure.…”