Genetic Deletion of the Prostaglandin EP4 Receptor in the Kidney Tubule of Adult Male Mice Has Mild Impact on Kidney Water Handling

Abstract

Prostaglandin E2 (PGE2) is an essential lipid mediator modulating several aspects of renal function. PGE2 acts via four PGE2 receptors, EP1‐EP4. EP4 is abundant in the kidney glomerulus, where it plays a role in renal hemodynamics. EP4 is also expressed in the collecting duct, and constitutive deletion of EP4 from this segment in mice suggests it plays a role in urine concentration. To assess the tubular role of EP4 in adult mice we generated a mouse model with doxycycline‐dependent deletion of EP4 along the renal tubule (Pax8Cre system) and assessed their renal phenotype regarding water handling. Two weeks after treatment with doxycycline, EP4 mRNA expression was reduced by >80% in the renal medulla (RT‐q‐PCR) of knockout mice compared to control mice. Under basal conditions, there were no significant differences between genotypes in food and water intake, bodyweight or plasma biochemistries. EP4 knockout males showed a small increase in basal urinary output and a decreased osmolality, concomitant with lower urinary Na+, K+, Cl‐, urea and creatinine concentrations. There were no differences between genotypes in their renal handling of water during water deprivation for 14 hours, or in their response to the vasopressin V2 receptor agonist dDAVP. In a water overloading test only the EP4 knockout females showed an increased urinary output after 1 hour of the water overload. In conclusion, EP4 in the renal tubule has a mild role in renal water handling. This new model provides a novel tool for assessing the role of EP4 in other aspects of kidney function or disease independently of potential developmental abnormalities or systemic effects.