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E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
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Abstract titles should be brief and reflect the content of the abstract.
This study aimed to investigate the therapeutic effect and underlying mechanism of Pegmolesatide, a novel long-acting EPO receptor modulator, on cardiac hypertrophy associated with chronic kidney disease (CKD).
In vivo: Rats with CKD induced by 5/6 nephrectomy were randomized to Sham, Sham + Pegmolesatide, CKD, and CKD + Pegmolesatide groups. After 12 weeks of treatment, we assessed cardiac function (echocardiography), histopathology of the heart and kidney (H&E, Masson, and WGA staining), hemoglobin levels, serum renal function markers, and the expression of hypertrophy-related proteins and key signaling molecules (ANP, BNP, β-MHC) by Western blot.
In vitro: H9c2 cardiomyocytes were divided into two experimental sets: a) basic interventions: Vihecle, Indoxyl Sulfate (IS), IS + Pegmolesatide, Pegmolesatide alone; and b) mechanistic interventions: co-treatment with CD131 agonist ARA290, STAT3 agonist Colivelin, or STAT3 inhibitor Stattic. Assessments included hypertrophy markers (ANP, BNP, β-MHC) and signaling molecules by qPCR/Western blot, cytoskeleton and surface area by phalloidin staining, pathway enrichment by transcriptome sequencing, EPOR-CD131 interaction by Co-IP, and mitochondrial membrane potential (JC-1) and ROS levels (DCFH-DA).
In vivo, Pegmolesatide significantly ameliorated cardiac structure and function in CKD rats, as evidenced by improved echocardiographic parameters, restored myocardial fiber alignment, and reduced inflammation, fibrosis, and cardiomyocyte cross-sectional area (Fig. 1). At the molecular level, Pegmolesatide downregulated hypertrophy markers (BNP, β-MHC) and suppressed STAT3 phosphorylation, indicating inhibition of the JAK2/STAT3 pathway (Fig. 2). In terms of renal histopathology, Pegmolesatide alleviated injuries such as tubular atrophy. With respect to functional indicators, however, no significant improvement was observed in serum creatinine, blood urea nitrogen, or urinary protein. (Fig. 2).
In vitro, Pegmolesatide counteracted indoxyl sulfate (IS)-induced cardiomyocyte hypertrophy, as shown by downregulation of ANP, BNP, and β-MHC, and restoration of the cytoskeleton (Fig. 3). Transcriptome sequencing implicated a pivotal role for the JAK2/STAT3 signaling pathway. Mechanistically, Pegmolesatide increased EPOR expression, suppressed CD131 overexpression, reduced EPOR-CD131 heterodimer formation, and thereby inhibited JAK2/STAT3 phosphorylation (Fig. 4, 5). Consequently, Pegmolesatide reversed IS-induced mitochondrial dysfunction by reducing ROS and restoring membrane potential. This benefit was blunted by the CD131 agonist ARA290, while the STAT3 inhibitor Stattic partially rescued this effect, indicating Pegmolesatide improves mitochondrial function via the CD131-STAT3 axis(Fig. 6).
Pegmolesatide ameliorates CKD-associated mitochondrial dysfunction and cardiomyocyte hypertrophy by antagonizing CD131/EPOR heterodimerization and suppressing the overactivation of the JAK2/STAT3 pathway (Fig. 7). This study demonstrates the pleiotropic effects of Pegmolesatide, providing a theoretical basis for its cardiorenal protective role in CKD patients. The content of this abstract was previously submitted to CCSN2025.
