Urine concentrating defect in prostaglandin EP1-deficient mice.
We investigated the role of the prostaglandin E(2) (PGE(2)) EP(1) receptor in modulating urine concentration as it is expressed along the renal collecting duct where arginine-vasopressin (AVP) exerts its anti-diuretic activity, and in the paraventricular and supraoptic nuclei of the hypothalamus where AVP is synthesized. The urine osmolality of EP(1)-null mice (EP(1)(-/-)) failed to match levels achieved by wild-type (WT) counterparts upon water deprivation (WD) for 24 h. This difference was reflected by higher plasma osmolality in WD EP(1)(-/-) mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP(1)(-/-) mice appeared equivalent to that of WD WT mice as determined by quantitative RT-PCR and immunohistochemistry. However, medullary interstitial osmolalities dropped significantly in EP(1)(-/-) mice following WD. Furthermore, urinary AVP levels of WD EP(1)(-/-) mice were significantly lower than those of WD WT mice. This deficit could be traced back to a blunted induction of hypothalamic AVP mRNA expression in WD EP(1)(-/-) mice as determined by quantitative RT-PCR. Administration of the AVP mimetic [deamino-Cys(1),D-Arg(8)]-vasopressin restored a significant proportion of the urine concentrating ability of WD EP(1)(-/-) mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP(1)(-/-) mice. These data suggest that PGE(2) modulates urine concentration by acting at EP(1) receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD.
Kennedy
Chris R J
CR
Department of Medicine, Ottawa Hospital, Ontario, Canada. ckennedy@uottawa.ca
Xiong
Huaqi
H
Rahal
Sherine
S
Vanderluit
Jacqueline
J
Slack
Ruth S
RS
Zhang
Yahua
Y
Guan
Youfei
Y
Breyer
Matthew D
MD
Hébert
Richard L
RL
D000818:Animals; D051399:Aquaporin 2 / Q000096:biosynthesis; D001127:Arginine Vasopressin / Q000096:biosynthesis; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D007671:Kidney Concentrating Ability / Q000235:genetics*; D051379:Mice; D018078:Receptors, Prostaglandin E / Q000172:deficiency*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D014868:Water Deprivation / Q000502:physiology*
D051399:Aquaporin 2; C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D001127:Arginine Vasopressin; D003894:Deamino Arginine Vasopressin