The EP3 receptor regulates water excretion in response to high salt intake

Abstract

The mechanisms by which prostanoids contribute to the maintenance of whole body water homeostasis are complex and not fully understood. The present study demonstrates that an EP3-dependent feedback mechanism contributes to the regulation of water homeostasis under high-salt conditions. Rats on a normal diet and tap water were placed in metabolic cages and given either sulprostone (20 μg·kg·day) or vehicle for 3 days to activate EP3 receptors in the thick ascending limb (TAL). Treatment was continued for another 3 days in rats given either 1% NaCl in the drinking water or tap water. Sulprostone decreased expression of cyclooxygenase 2 (COX-2) expression by ∼75% in TAL tubules from rats given 1% NaCl concomitant with a ∼60% inhibition of COX-2-dependent PGE levels in the kidney. Urine volume increased after ingestion of 1% NaCl but was reduced ∼40% by sulprostone. In contrast, the highly selective EP3 receptor antagonist L-798106 (100 μg·kg·day), which increased COX-2 expression and renal PGE production, increased urine volume in rats given 1% NaCl. Sulprostone increased expression of aquaporin-2 (AQP2) in the inner medullary collecting duct plasma membrane in association with an increase in phosphorylation at Ser269 and decrease in Ser261 phosphorylation; antagonism of EP3 with L-798106 reduced AQP2 expression. Thus, although acute activation of EP3 by PGE in the TAL and collecting duct inhibits the Na-K-2Cl cotransporter and AQP2 activity, respectively, chronic activation of EP3 in vivo limits the extent of COX-2-derived PGE synthesis, thereby mitigating the inhibitory effects of PGE on these transporters and decreasing urine volume.

Genetic Variants in PGE2 Receptors Modulate the Risk of Nephrosclerosis and Clinical Outcomes in These Patients

“…Variability in the PTGER3 gene locus has not been extensively studied, and consequently there is no data regarding the functional impact of polymorphisms. We do know, however, that the administration of EP3 antagonists in vivo increases COX-2-mediated PGE2 expression in the kidney, whilst the receptor activation decreases PGE2 levels [ 20 ]. This is relevant to the development of nephrosclerosis, as PGE2 contributes significantly to kidney disease, as it is involved in albuminuria, growth/fibrosis, and the activation of the renin–angiotensin–aldosterone system (RAAS) [ 21 ].…”

Associations of E‐proteinoid 3 receptor genetic polymorphisms with salt sensitivity, longitudinal blood pressure changes, and hypertension incidence in Chinese adults

“…Furthermore, multiple studies have highlighted the involvement of PTGER3 in renal sodium excretion. For instance, Hao et al 29 discovered that PTGER3 activation under high salt conditions inhibits the activity of Na + -K + -2Cl − cotransporter in the mTAL and aquaporin-2 in the collecting ducts, leading to increased urine output. Rytved et al 30 also reported that PTGER3 activation in the skin epithelium of frogs suppresses the stimulating effect of antidiuretic hormones on intraepithelial Na + transport.…”

“…Furthermore, multiple studies have highlighted the involvement of PTGER3 in renal sodium excretion. For instance, Hao et al 29 . discovered that PTGER3 activation under high salt conditions inhibits the activity of Na + ‐K + ‐2Cl − cotransporter in the mTAL and aquaporin‐2 in the collecting ducts, leading to increased urine output.…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…In rats, the EP3 receptor is reported to regulate water excretion in response to high salt intake; it decreases collecting duct-water permeability and increases water excretion. High-salt treatment increased COX-2–dependent PGE 2 production when the EP3 receptor was blocked by L-798106 in the thick ascending limb, whereas urine output was decreased when the EP3 receptor was activated by sulprostone (EP3 > EP1 agonist) ( Hao et al, 2016 ). EP2 and EP4 receptors are reported to bypass vasopressin signaling and increase water reabsorption ( Olesen and Fenton, 2013 ).…”