2. Academic Validation
  3. Inhibiting mPGES-2 impedes renal cyst growth in mice with polycystic kidney disease

Inhibiting mPGES-2 impedes renal cyst growth in mice with polycystic kidney disease

  • Acta Pharmacol Sin. 2025 Oct 17. doi: 10.1038/s41401-025-01664-x.
Dan-Dan Zhong # 1 2,  Cheng Hu # 1 2 3 4,  Lan-Lan Zhao # 1 2 3,  Yan Shen 1,  Ru-Meng Zhang 5,  Ying Liu 6,  Bu-Hui Liu 1 2,  Wen Su 7 8,  Bao-Xue Yang 9,  Hui Xiong 10,  Dong Guo 1,  Dong Sun 11,  Ying-Ying Zou 12 13,  Ying Sun 14 15
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, 221004, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.
  • 3 Clinical Research Center for Kidney Disease, Xuzhou Medical University, Xuzhou, 221004, China.
  • 4 Taicang Loujiang New Town Hospital, Suzhou, 215400, China.
  • 5 Department of Pharmacology, Xuzhou Central Hospital, Xuzhou, 221009, China.
  • 6 Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
  • 7 Department of Pathophysiology, Shenzhen University, Shenzhen, 518060, China.
  • 8 Shenzhen University Health Science Center, Shenzhen University, Shenzhen, 518060, China.
  • 9 State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
  • 10 Department of Urology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Ji-nan, 250021, China.
  • 11 Clinical Research Center for Kidney Disease, Xuzhou Medical University, Xuzhou, 221004, China. sundongxz@126.com.
  • 12 Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, 221004, China. zouyy2378@xzhmu.edu.cn.
  • 13 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. zouyy2378@xzhmu.edu.cn.
  • 14 Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, 221004, China. yingsun@xzhmu.edu.cn.
  • 15 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. yingsun@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 41107403 DOI: 10.1038/s41401-025-01664-x
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) 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 (mPGES-2) is a unique bifunctional enzyme that catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) or to malondialdehyde (MDA) in conjunction with heme. PGE2 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 (Ptges2-/-) mice with Ksp-Cre; PKD1flox/+ mice to generate mPGES-2 knockout ADPKD (Ptges2-/-; PKD) 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 (40, 80, and 160 μM) 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 PGE2 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 PGE2-EP4, 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.

Keywords

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

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