Iguratimod prevents renal fibrosis in unilateral ureteral obstruction model mice by suppressing M2 macrophage infiltration and macrophage–myofibroblast transition

Abstract

Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-β and iguratimod or SRC inhibitors in vitro, suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage–myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.

Keywords:

• Iguratimod
• macrophage infiltration
• macrophage–myofibroblast transition
• renal fibrosis
• unilateral ureteral obstruction

Acknowledgments

We thank Prof. Xiaoyan Zhu of the Naval Military Medical University for providing guidance on our study. We are grateful to Simcere for providing us with iguratimod and part of the research funding, and to Editage for the English language editing services. Additionally, we sincerely appreciate Professor Xin Ni from the International Joint Research Center of Medical Metabolomics at Xiangya Hospital, Central South University, for providing us with research platforms and material assistance during the experimental supplementation phase.

Authors’ contributions

Yueyuan Zhou: Data curation, Investigation, Methodology, Visualization, Writing – original draft, and Writing – review & editing; Zhilan Li: Validation and Investigation; Shenyi Yu: Investigation; Xuan Wang: Writing – review & editing; Tingting Xie: Methodology; Weiru Zhang: Conceptualization and Funding acquisition.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [81974090], the Research Project of Hunan Provincial Health Commission [202116000446], the Natural Science Foundation of Hunan Province (Science and health joint Program) [2022JJ70086 and 2023JJ30973], Hunan Provincial Innovation Team Project [2018RS3030], the Fundamental Research Funds for the Central Universities of Central South University [2020zzts869] and Simcere Corporation.