Urine concentrating defect in prostaglandin EP1-deficient mice

Abstract

We investigated the role of the prostaglandin E2(PGE2) EP1receptor 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 PGE2modulates urine concentration by acting at EP1receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD.