2. Academic Validation
  3. Pegmolesatide ameliorates indoxyl sulfate-induced cardiomyocyte hypertrophy through modulating the EPOR-CD131-dependent JAK2/STAT3 signaling pathway

Pegmolesatide ameliorates indoxyl sulfate-induced cardiomyocyte hypertrophy through modulating the EPOR-CD131-dependent JAK2/STAT3 signaling pathway

  • Int Immunopharmacol. 2025 Oct 14:167:115643. doi: 10.1016/j.intimp.2025.115643.
Xinyu Zhang 1,  Sufang Li 2,  Tingru Lin 1,  Liangying Gan 1,  Li Zhu 3,  Li Zuo 1
Affiliations

Affiliations

  • 1 Department of Nephrology, Peking University People's Hospital, 11 Xizhimennan Street, Xicheng District, Beijing, 100044, China.
  • 2 Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, 11 Xizhimennan Street, Xicheng District, Beijing 100044, China.
  • 3 Department of Nephrology, Peking University People's Hospital, 11 Xizhimennan Street, Xicheng District, Beijing, 100044, China. Electronic address: zhuli3714@126.com.
PMID: 41092772 DOI: 10.1016/j.intimp.2025.115643
Abstract

Background: Cardiovascular events remain the leading cause of mortality in chronic kidney disease (CKD). Pegmolesatide(P), a novel long-acting EPO receptor modulator, shows cardiovascular benefits in clinical studies. This study aims to demonstrate Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer and to explore its cardioprotective mechanisms against indoxyl sulfate (IS)-induced cardiomyocyte hypertrophy.

Methods: H9c2 cardiomyocytes were assigned to different treatment groups (vehicle, IS, IS+P, P) and RNA Sequencing was performed to identify dysregulated signaling pathways. Mechanistic exploration groups supplemented with CD131 agonist ARA290, STAT3 Activator Colivelin, or STAT3 Inhibitor Stattic for rescue experiments. Analyses included real-time qPCR/Western blot for cardiac hypertrophy markers and EPOR-CD131/JAK2/STAT3 axis components, phalloidin staining for cell size and co-immunoprecipitation (Co-IP) for EPOR-CD131 heterodimerization.

Results: Pegmolesatide significantly attenuated IS-induced cardiomyocyte hypertrophy, as evidenced by suppressed expression of cardiac hypertrophy markers (ANP, BNP, and β-MHC), reduced cell surface area, and improved cytoskeletal organization(P < 0.05). Mechanistically, Pegmolesatide upregulated EPOR expression while suppressing CD131 expression and activation of the JAK2/STAT3 signaling. Co-IP analysis demonstrated that Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer. Functional rescue experiments showed that the cardioprotective effects of Pegmolesatide were reversed by CD131 agonist ARA290 or STAT3 Activator Colivelin. Notably, combined treatment with ARA290 and STAT3 Inhibitor Stattic partially restored its anti-hypertrophic activity.

Conclusion: Pegmolesatide exerts protective effects against IS-induced cardiomyocyte hypertrophy by inhibiting the EPOR-CD131/JAK2/STAT3 signaling axis. It may be a promising strategy for CKD-related cardiovascular complications.

Keywords

Cardiomyocyte hypertrophy; EPOR-CD131 heterodimer; Indoxyl sulfate; JAK2/STAT3 signaling pathway; Pegmolesatide.

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