Deletion of the prostaglandin EP4 receptor in the kidney tubule of mature mice alters kidney water handling only in males

Prostaglandin E2 (PGE₂) is a lipid mediator modulating several aspects of kidney function. PGE₂ acts via four prostanoid receptors, EP1 to EP4. In renal tubules, EP4 has very low expression, yet a role for EP4 in maintaining water balance has been proposed. The major aim of this study was to clarify the role of the EP4 receptor in the kidney tubule of adult mice for body water homeostasis. To examine this, a mouse model with doxycycline-dependent deletion of EP4 along the renal tubule (Pax8Cre system) was developed and phenotyped with respect to water handling. Two weeks after doxycycline treatment, EP4 mRNA expression (RT-qPCR) was reduced by >80% in the medulla of male and female knockout mice (<i>EP4</i>^-/-) compared with controls (<i>EP4</i>^+/+). With free access to water, there were no detectable differences between genotypes in food intake, body weight, or plasma biochemistries. Male, but not female, <i>EP4</i>^-/- mice had a small but significantly higher basal urinary output with decreased osmolality, concomitant with lower urinary Na⁺, K⁺, Cl^-, urea, and creatinine concentrations. The urea channel UT-A1 was reduced in the medulla, but otherwise no major differences in the levels of proteins involved in water balance were observed between genotypes. There were no differences between genotypes in their ability to concentrate urine during a 14-h water restriction or after treatment with the vasopressin V2 receptor agonist 1-deamino-8-d-arginine-vasopressin. <i>EP4</i>^-/- mice of both sexes excreted an acute water load similarly to control mice. In conclusion, EP4 in the renal tubule has a mild role in renal water handling, but only in male mice. This new model provides a novel tool for assessing the role of EP4 in kidney tubule function in various (patho)physiological conditions independently of developmental abnormalities or systemic effects.<b>NEW & NOTEWORTHY</b> Acting through the EP1-EP4 receptors, prostaglandin E2 (PGE₂) modulates various aspects of kidney function. Despite extremely low expression in the collecting duct, EP4 has been proposed to play a key role in regulation of Aquaporin-2 and water balance. In this study, we show that EP4 only plays a mild role in kidney water handling in male mice, calling into question the standard concepts presented in physiology textbooks regarding PGE₂ actions on the collecting duct.