PGE2 binding to EP2 promotes ureteral stone expulsion by relaxing ureter via the cAMP-PKA pathway

TL;DR

This study shows that PGE2 helps expel ureteral stones by relaxing the ureter through the cAMP-PKA pathway.

Contribution

The study identifies EP2 as the key receptor for PGE2-induced ureteral relaxation in stone expulsion.

Findings

PGE2 induces concentration-dependent ureteral relaxation, with a maximum rate of 70.94 ± 4.57% at 30µM.

EP2 antagonists block PGE2's effect, while EP4 antagonists do not.

Obstructed ureters show increased mPGES-1 and EP2 protein expression.

Abstract

This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.

By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes.

The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA.

PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones.

The online version contains supplementary material available at 10.1186/s12894-024-01504-w.

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