Urine concentrating defect in prostaglandin EP₁-deficient mice

Abstract

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 argininevasopressin (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 (EP1 Ϫ/Ϫ ) 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 Ϫ/Ϫ mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP Ϫ/Ϫ mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP 1 Ϫ/Ϫ 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. vasopressin; urine concentration; prostaglandin E 2; EP1 receptor URINE CONCENTRATION IS A HIGHLY regulated process requiring the coordinated actions of a number of hormones at several tissue locales (2). The body responds to acute volume depletion, infection, or hyperosmolality by stimulating the production of antidiuretic hormone, arginine-vasopressin (AVP), within the hypothalamic paraventricular (PVN) and supraoptic (SON) neurons. AVP is then processed, stored, and secreted into the venous flow by the posterior pituitary to interact with renal V 2 receptors located in the principal cells of the collecting duct to promote aquaporin-2 (AQP2)-dependent water reabsorption (25). Many of these steps are subject to modulation by endocrine factors such as ANG II, catecholamines, as well as certain metabolites of the cyclooxygenase (COX) pathway, the prostaglandins (PGs) (2). Accordingly, renal prostaglandin E 2 (PGE 2 ) antagonizes the actions of AVP since NSAIDs transiently enhance urine concentration (1). Direct evidence for the underlying mechanism was provided by who demonstrated that PGE 2 attenuates vasopressin-stimulated osmotic water reabsorption in isolated microperfused rabbit collecting ducts. Subsequent cell culture studies showed that PGE 2 counteracts AVP action by enhancing AQP2 endocytotic uptake from the apical plasma membrane (33). On the other hand, recent studies showed that inhibition of COX by indomethacin reduced renal AQP2 expression in rats, implying that PGs may actually help maintain AQP2 levels (20).In addition to the well-known renal effects of PGs on urine concentration, other evidence suggests that COX-derived products could influence this process by acting at central locales. Early studies showed that AVP release was stimulated by PGE 2 in the rat neurohypophysis (32). Ishikawa et al. (17) showed a reduced release of AVP in response to either hyperosmotic exposure or ANG II in guinea pig hypothalamoneurohypophyseal cultures following treatment with indomethacin. Finally, an intracerebroventri...

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…In experimental glomerulonephritis, there was reduced urine osmolality, and overall renal damage was more acute in EP 1 (Ϫ/Ϫ) mice (Rahal et al, 2006). PGE 2 , via EP 1 , modulates urine concentration not modulated in the renal collecting duct but within the hypothalamus to promote arginine vasopressin biosynthesis in response to water deprivation (Kennedy et al, 2007). In a model of bladder outlet obstruction, detrusor hyperactivity was negligible in EP 1 receptor knockout mice (Schröder et al, 2004).…”

Prostanoids in health and disease

“…EP 1 , expressed exclusively in collecting ducts, mediates PGE 2 -dependent inhibition of salt and water absorption. EP 1 -deficient mice have a urine concentration defect due to decreased vasopressin release, resulting in hypotension (16). EP 2 mRNA is present at low levels in the descending thin limb of Henle and the vasa recta of the outer medulla; mice deficient in EP 2 develop salt-sensitive hypertension.…”

Studies on localization and function of annexin A4a within urinary bladder epithelium using a mouse knockout model

“…Since urine has osmolalities that can vary from 50 to 1,000 mosmol/kg in humans and from 2,000 to 4,000 mosmol/kg in the mouse (16), widely fluctuating urea and NH 3 concentrations, and proton concentrations that vary over many orders of magnitude (pH 4.5-9), the bladder permeability barrier plays an essential role in osmotic and metabolic homeostasis. It has been shown that anxA4 binding and self-polymerization on membranes results in a rigidification of the lipids in the bound leaflet, with a resulting reduction in the permeability of the membrane to water and protons (11).…”