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Urine concentrating defect in prostaglandin EP₁-deficient mice

¹Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital, Ottawa Health Research Institute, ²Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and ³Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee

Submitted 4 May 2005 ; accepted in final form 25 July 2006

We investigated the role of the prostaglandin E₂ (PGE₂) EP₁ 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 EP₁-null mice (EP₁^–/–) 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 EP₁^–/– mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP₁^–/– mice appeared equivalent to that of WD WT mice as determined by quantitative RT-PCR and immunohistochemistry. However, medullary interstitial osmolalities dropped significantly in EP₁^–/– mice following WD. Furthermore, urinary AVP levels of WD EP₁^–/– 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 EP₁^–/– mice as determined by quantitative RT-PCR. Administration of the AVP mimetic [deamino-Cys¹,D-Arg⁸]-vasopressin restored a significant proportion of the urine concentrating ability of WD EP₁^–/– mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP₁^–/– mice. These data suggest that PGE₂ modulates urine concentration by acting at EP₁ receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD.

vasopressin; urine concentration; prostaglandin E₂; EP₁ receptor

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