Opioid receptor-like 1 stimulation in the collecting duct induces aquaresis through vasopressin-independent aquaporin-2 downregulation.
Nociceptin, the endogenous ligand of the inhibitory G protein-coupled opioid receptor-like 1 receptor, produces aquaresis (i.e., increases the excretion of solute-free urine) in rats. However, the mechanism underlying this effect has not yet been explained. Using immunohistochemistry, we found the opioid receptor-like 1 receptor in the rat kidney colocalized with the vasopressin-regulated water channel aquaporin-2 in inner medullary collecting ducts. We investigated the aquaretic effect of opioid receptor-like 1 receptor stimulation by infusing the selective nociceptin analog ZP120C; volume depletion was prevented by computer-driven, servo-controlled intravenous volume replacement with 50 mM glucose. ZP120C induced a marked and sustained aquaresis in normal and congestive heart failure rats in the absence of changes in vasopressin plasma concentrations. The ZP120C-induced aquaresis was associated with downregulation of the aquaporin-2 protein level in both rat groups, suggesting that opioid receptor-like 1 receptor stimulation produces aquaresis by inhibiting the vasopressin type-2 receptor-mediated stimulation on collecting duct water reabsorption. However, substantial amounts of PKA-mediated serine 256 phosphorylated aquaporin-2 were still present after 4 h of ZP120C treatment. Furthermore, neither preincubation with nociceptin nor ZP120C inhibited vasopressin-mediated cAMP accumulation in isolated collecting ducts. We conclude that renal opioid receptor-like 1 receptor stimulation in normal and congestive heart failure rats produces aquaresis by a direct renal effect, via aquaporin-2 downregulation, through a mechanism not involving inhibition of vasopressin type-2 receptor-mediated cAMP production.
Hadrup
Niels
N
Department of Pharmacology, University of Copenhagen, 2200 Copenhagen N, Denmark. niels.hadrup@farmakol.ku.dk
Petersen
Jørgen S
JS
Praetorius
Jeppe
J
Meier
Eddi
E
Graebe
Martin
M
Brønd
Lone
L
Staahltoft
Dennis
D
Nielsen
Søren
S
Christensen
Sten
S
Kapusta
Daniel R
DR
Jonassen
Thomas E N
TE
D000818:Animals; D051399:Aquaporin 2; D020346:Aquaporins / Q000096:biosynthesis* / Q000378:metabolism; D015536:Down-Regulation; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007685:Kidney Tubules, Collecting / Q000502:physiology*; D008297:Male; D018847:Opioid Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000096:biosynthesis*; D014556:Urine / Q000737:chemistry; D014665:Vasodilator Agents / Q000494:pharmacology*; D014667:Vasopressins / Q000494:pharmacology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D051399:Aquaporin 2; D020346:Aquaporins; D018847:Opioid Peptides; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D014667:Vasopressins; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C496025:Aqp2 protein, rat; C000722285:Oprl1 protein, rat