PGE2 Binding to EP2 Promotes Ureteral Stone Expulsion by Relaxing Ureter Via the CAMP-PKA Pathway

Overview

Journal BMC Urol

Publisher Biomed Central

Specialty Urology

Date 2024 Jun 8

PMID 38851678

Authors

Hao Su

Wenyan Zhou

Weiming Chen

Ke Yang

Meng Yang

Hu He

Cheng Qian

Dongbo Yuan

Kehua Jiang

Jianguo Zhu

Affiliations

Soon will be listed here.

Abstract

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

Methods: 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.

Results: 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.

Conclusions: 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.

References

Cole R, Fry C, Shuttleworth K . The action of the prostaglandins on isolated human ureteric smooth muscle. Br J Urol. 1988; 61(1):19-26. DOI: 10.1111/j.1464-410x.1988.tb09155.x. View

Jang Y, Kim M, Hwang S . Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception. J Neuroinflammation. 2020; 17(1):30. PMC: 6975075. DOI: 10.1186/s12974-020-1703-1. View

Bai X, Ihara E, Otsuka Y, Tsuruta S, Hirano K, Tanaka Y . Involvement of different receptor subtypes in prostaglandin E2-induced contraction and relaxation in the lower esophageal sphincter and esophageal body. Eur J Pharmacol. 2019; 857:172405. DOI: 10.1016/j.ejphar.2019.172405. View

Norel X, Sugimoto Y, Ozen G, Abdelazeem H, Amgoud Y, Bouhadoun A . International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions. Pharmacol Rev. 2020; 72(4):910-968. PMC: 7509579. DOI: 10.1124/pr.120.019331. View

Gizem Ergul A, Gur Maz T, Kretzer C, Olgac A, Jordan P, Caliskan B . Novel potent benzimidazole-based microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C synthase. Eur J Med Chem. 2022; 231:114167. DOI: 10.1016/j.ejmech.2022.114167. View

Wanggren K, Stavreus-Evers A, Olsson C, Andersson E, Gemzell-Danielsson K . Regulation of muscular contractions in the human Fallopian tube through prostaglandins and progestagens. Hum Reprod. 2008; 23(10):2359-68. DOI: 10.1093/humrep/den260. View

Hou C, Lin Y, Juang H, Chang P, Chen C, Yang P . Effect of ureteral calculus in outpatients receiving semirigid ureteroscope laser lithotripsy. Medicine (Baltimore). 2020; 99(10):e19324. PMC: 7478698. DOI: 10.1097/MD.0000000000019324. View

Harris S, Padilla J, Koumas L, Ray D, Phipps R . Prostaglandins as modulators of immunity. Trends Immunol. 2002; 23(3):144-50. DOI: 10.1016/s1471-4906(01)02154-8. View

Su H, Liu H, Yang K, Chen W, Yuan D, Wang W . Construction of a novel rabbit model of ureteral calculi implanted with flowable resin. BMC Urol. 2022; 22(1):105. PMC: 9295447. DOI: 10.1186/s12894-022-01056-x. View

10.

Kanda H, Kobayashi K, Yamanaka H, Okubo M, Dai Y, Noguchi K . Localization of prostaglandin E2 synthases and E-prostanoid receptors in the spinal cord in a rat model of neuropathic pain. Brain Res. 2020; 1750:147153. DOI: 10.1016/j.brainres.2020.147153. View

11.

Xiao L, Liu H, Di H, Chen L, Zhou Q, Yu X . Angtensin II elicits a cAMP-dependent intestinal anion secretion by stimulating PGE2 release through AT1 subtype receptors in rat ileum. Biochem Biophys Res Commun. 2017; 494(1-2):207-212. DOI: 10.1016/j.bbrc.2017.10.052. View

12.

Hokanson J, Langdale C, Sridhar A, Grill W . OAB without an overactive bladder in the acute prostaglandin E2 rat model. Am J Physiol Renal Physiol. 2017; 313(5):F1169-F1177. PMC: 5792156. DOI: 10.1152/ajprenal.00270.2017. View

13.

Dai J, Pearle M . Diet and Stone Disease in 2022. J Clin Med. 2022; 11(16). PMC: 9410446. DOI: 10.3390/jcm11164740. View

14.

Ye Z, Xiao H, Liu G, Qiao Y, Zhao Y, Ji Z . Subcutaneous Adipose Tissue Accumulation Is an Independent Risk Factor of Urinary Stone in Young People. Front Endocrinol (Lausanne). 2022; 13:865930. PMC: 9280630. DOI: 10.3389/fendo.2022.865930. View

15.

Li W, Lu J, Zhang C, Wang W, Ying H, Myatt L . PGE2 vs PGF2α in human parturition. Placenta. 2021; 104:208-219. DOI: 10.1016/j.placenta.2020.12.012. View

16.

Seo M, Oh D . Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis. Prog Lipid Res. 2017; 66:50-68. DOI: 10.1016/j.plipres.2017.04.003. View

17.

Kim J, Park E, Seo S, Park Y, Hwang T . Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol. 2006; 175(5):1773-6. DOI: 10.1016/S0022-5347(05)00992-4. View

18.

Campschroer T, Zhu Y, Duijvesz D, Grobbee D, Lock M . Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014; (4):CD008509. DOI: 10.1002/14651858.CD008509.pub2. View

19.

Michael J, Gavrila A, Nayak A, Pera T, Liberato J, Polischak S . Cooperativity of E-prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle. FASEB J. 2019; 33(4):4780-4789. PMC: 6436661. DOI: 10.1096/fj.201801959R. View

20.

Sharma G, Pareek T, Kaundal P, Tyagi S, Singh S, Yashaswi T . Comparison of efficacy of three commonly used alpha-blockers as medical expulsive therapy for distal ureter stones: A systematic review and network meta-analysis. Int Braz J Urol. 2021; 48(5):742-759. PMC: 9388169. DOI: 10.1590/S1677-5538.IBJU.2020.0548. View