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作者

Dan-dan Zhong Cheng Hu Lan-lan Zhao Yan Shen Ru-meng Zhang Ying Liu Bu-hui Liu Wen Su Bao-xue Yang Hui Xiong Dong Guo Dong Sun Ying-ying Zou null Ying Sun

作者单位

⁹State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China ⁴Taicang Loujiang New Town Hospital, Suzhou, 215400, China ⁶Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China ⁷Department of Pathophysiology, Shenzhen University, Shenzhen, 518060, China ¹Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, 221004, China ⁸Shenzhen University Health Science Center, Shenzhen University, Shenzhen, 518060, China ⁵Department of Pharmacology, Xuzhou Central Hospital, Xuzhou, 221009, China ¹⁰Department of Urology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Ji-nan, 250021, China ²Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China ³Clinical Research Center for Kidney Disease, Xuzhou Medical University, Xuzhou, 221004, China

刊名

Acta Pharmacologica Sinica

年份

2025

ISSN

1671-4083

关键词

ADPKD mPGES-2 PGE₂ proliferation β-catenin/STAT3 SZ0232

摘要

Autosomal dominant polycystic kidney disease is characterized by the development of multiple fluid-filled cysts in the kidneys, resulting in progressive decline and failure of renal function. Microsomal prostaglandin E synthase-2 is a unique bifunctional enzyme that catalyzes the conversion of prostaglandin H to prostaglandin E or to malondialdehyde in conjunction with heme. PGE and MDA are key mediators that regulate cell growth and proliferation, respectively. In this study, we elucidated...更多

Autosomal dominant polycystic kidney disease is characterized by the development of multiple fluid-filled cysts in the kidneys, resulting in progressive decline and failure of renal function. Microsomal prostaglandin E synthase-2 is a unique bifunctional enzyme that catalyzes the conversion of prostaglandin H to prostaglandin E or to malondialdehyde in conjunction with heme. PGE and MDA are key mediators that regulate cell growth and proliferation, respectively. In this study, we elucidated the functional role of mPGES-2 in ADPKD. By performing Western blot and immunohistochemical staining on the kidneys of patients with PKD and healthy controls, we showed that the expression levels of mPGES-2 markedly increased. We then crossed mPGES-2 knockout mice with Ksp-Cre; pkd1 mice to generate mPGES-2 knockout ADPKD mice. We showed that mPGES-2 depletion mitigated ADPKD progression in a mouse model. These findings were corroborated by in vitro experiments in embryonic kidney cells: the application of the mPGES-2 inhibitor SZ0232 effectively suppressed cyst growth, suggesting a potential therapeutic option for ADPKD. Analysis of mPGES-2 metabolites revealed that mPGES-2 deficiency led to a reduction in PGE production, which has not been detected in other renal diseases, likely because of the diminished heme levels in ADPKD kidneys. Moreover, mPGES-2 was implicated in the regulation of the downstream signaling pathway involving β-catenin/STAT3-c-Myc via PGE–EP, which promoted abnormal proliferation of renal tubular epithelial cells and influenced cyst formation. Our findings suggest that targeting mPGES-2 is a viable therapeutic strategy for the management of ADPKD.收起

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