Academic Journal
EP3 receptor mediates calcium oxalate kidney stone formation via Ca²⁺/AKT and necroinflammation.
| Τίτλος: | EP3 receptor mediates calcium oxalate kidney stone formation via Ca²⁺/AKT and necroinflammation. |
|---|---|
| Συγγραφείς: | Leng J; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Li Y; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Tang X; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Song Z; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Lv H; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Han H; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Wen N; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Fan J; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Zhang A X; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Zhang L; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Zhang B X; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Zhou F; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Guo T; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China., Liu Q; Shenyang Red-cross Hospital, 389 Zhongshan Rd, Shenyang, 110013, China., Gao B; Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang, 110034, China. gaobingdr@hotmail.com.; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang, 110034, China. gaobingdr@hotmail.com. |
| Πηγή: | Urolithiasis [Urolithiasis] 2026 Aug 14; Vol. 54 (1). Date of Electronic Publication: 2026 Aug 14. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Springer Country of Publication: Germany NLM ID: 101602699 Publication Model: Electronic Cited Medium: Internet ISSN: 2194-7236 (Electronic) Linking ISSN: 21947228 NLM ISO Abbreviation: Urolithiasis Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Berlin : Springer, [2013]- |
| Ιατρικοί όροι (MeSH): | Calcium Oxalate*/metabolism , Proto-Oncogene Proteins c-akt*/metabolism , Receptors, Prostaglandin E, EP3 Subtype*/metabolism , Receptors, Prostaglandin E, EP3 Subtype*/antagonists & inhibitors , Kidney Calculi*/metabolism , Kidney Calculi*/pathology , Nephrolithiasis*/metabolism, Calcium/metabolism ; HMGB1 Protein/metabolism ; Inflammation/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Animals ; Humans ; Mice ; Male ; Disease Models, Animal ; Cell Line |
| Περίληψη: | Kidney stone disease is a prevalent urological condition with rising incidence and high recurrence rates, yet effective pharmacological interventions remain lacking [1] Prostaglandin E₂ (PGE₂) and its receptor EP3 have been implicated in inflammatory kidney injury [1-3], but their role in nephrolithiasis is unclear. This study investigates the role and mechanism of EP3 in calcium oxalate (CaOx) stone formation using in vitro and in vivo models. EP3 expression was significantly upregulated in CaOx-stimulated human renal tubular epithelial cells (HK-2) and in kidney tissues of glyoxylate-induced nephrolithiasis mice. Treatment with the EP3 antagonist DG041 in vitro reduced crystal adhesion, decreased HMGB1 release, and suppressed IL-6 and TNF-α expression. Mechanistically, EP3 antagonism inhibited aberrant intracellular Ca2⁺ elevation and reduced AKT phosphorylation. Virtual screening identified Astragaloside A as a potential EP3 inhibitor. Astragaloside A recapitulated the protective effects of DG041, attenuating crystal adhesion, inflammation, and necroinflammation both in vitro and in vivo. These findings indicate that EP3 mediates crystal-induced renal tubular injury and inflammation via the Ca2⁺/AKT signaling axis. Targeting EP3 may interrupt the "crystal‑injury‑inflammation" cycle in nephrolithiasis, offering a new therapeutic strategy. This study is the first to demonstrate that the EP3 receptor mediates calcium oxalate kidney stone formation through the Ca2⁺/AKT signaling pathway and necroinflammation. EP3 antagonism reduces crystal adhesion, HMGB1 release, and inflammation. Virtual screening identifies astragaloside A as a novel EP3 inhibitor with protective effects in vitro and in vivo, highlighting EP3 as a promising therapeutic target. (© 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) |
| Competing Interests: | Declarations. Competing interests: The authors declare no competing interests. Disclaimers: The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. |
| References: | Kidney Int. 2009 Feb;75(3):278-84. (PMID: 18843255) Am J Physiol Renal Physiol. 2000 Jan;278(1):F130-7. (PMID: 10644664) J Urol. 1988 Mar;139(3):549-51. (PMID: 3422697) EBioMedicine. 2019 Dec;50:366-378. (PMID: 31735555) Redox Biol. 2018 Jun;16:414-425. (PMID: 29653411) J Cell Sci. 2007 Jan 15;120(Pt 2):213-8. (PMID: 17215450) Nat Rev Immunol. 2024 Oct;24(10):703-719. (PMID: 38684933) Exp Mol Pathol. 2020 Aug;115:104450. (PMID: 32417393) Am J Med Sci. 2001 Mar;321(3):181-90. (PMID: 11269794) Trends Biochem Sci. 2025 Jan;50(1):46-60. (PMID: 39532582) Microbiome. 2025 Dec 15;14(1):35. (PMID: 41398611) Redox Biol. 2023 May;61:102648. (PMID: 36871182) Int Immunopharmacol. 2025 Mar 26;150:114250. (PMID: 39952007) Nat Rev Dis Primers. 2016 Feb 25;2:16008. (PMID: 27188687) Annu Rev Physiol. 2001;63:579-605. (PMID: 11181968) J Adv Res. 2026 May;83:183-218. (PMID: 40752681) Am J Physiol. 1996 May;270(5 Pt 2):F912-8. (PMID: 8928854) Biochim Biophys Acta Mol Basis Dis. 2025 Jun;1871(5):167791. (PMID: 40086520) Nat Rev Nephrol. 2020 Dec;16(12):736-746. (PMID: 32753740) J Cell Mol Med. 2024 Oct;28(20):e70180. (PMID: 39462270) Kidney Int. 2023 Jan;103(1):100-114. (PMID: 36087809) Clin J Am Soc Nephrol. 2015 Jul 7;10(7):1257-72. (PMID: 25287933) Biochem Pharmacol. 2020 Oct;180:114147. (PMID: 32653589) Nat Rev Nephrol. 2017 Apr;13(4):226-240. (PMID: 28218266) |
| Grant Information: | 2023-BSBA-292 Doctoral Research Startup Project of the Liaoning Provincial Science and Technology Plan Joint Fund; 82300865 National Natural Science Foundation of China; 82470798 National Natural Science Foundation of China |
| Contributed Indexing: | Keywords: Calcium oxalate; EP3 receptor; Kidney stones; Necroinflammation |
| Substance Nomenclature: | 2612HC57YE (Calcium Oxalate) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 0 (Receptors, Prostaglandin E, EP3 Subtype) SY7Q814VUP (Calcium) 0 (HMGB1 Protein) 0 (Tumor Necrosis Factor-alpha) |
| Entry Date(s): | Date Created: 20260814 Date Completed: 20260814 Latest Revision: 20261008 |
| Update Code: | 20261008 |
| DOI: | 10.1007/s00240-026-02030-0 |
| PMID: | 42599300 |
| Βάση Δεδομένων: | MEDLINE |
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