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Abstract: FR-PO687

Mechanistic Study of Celastrol-Mediated Inhibition of Macrophage M1 Polarization in IgA Nephropathy via Downregulating ECM1

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Zhao, Juanyong, Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
  • Xia, Ming, Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
  • Tang, Xunzi, Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
  • Fan, Xinyan, Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
  • Liu, Hong, Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
Background

Macrophages play a vital part in amplifying the inflammatory cascade in IgA nephropathy (IgAN), but the potential mechanism and targeted treatment strategies still need to be explored. The aim of this study is to investigate the therapeutic effect of celastrol (CLT) on IgAN, as well as the mechanism of celastrol-mediated inhibition of macrophage M1 polarization in IgA Nephropathy via down-regulating ECM1.

Methods

We established an IgAN mouse model treated with CLT and an M1 macrophage model induced by LPS in Raw 264.7 in vitro. The proteinuria, serum creatinine levels, renal lesions, and infiltration of M1 macrophages in mice were detected. The macrophage markers such as M1 (iNOS) and M2 (Arg-1) expression levels in vitro were checked, as well as expression situation of inflammatory factors such as IL-6 and TNF- α. The expression of ECM1 in renal biopsy of patients was observed and its clinical significance was analyzed. We detected the activation of the ECM1/STAT5 pathway in IgAN mice and M1 macrophage models. And we constructed stable transfected cells with ECM1 overexpression to detect the changes in macrophage M1 polarization after CLT treatment, as well as the expression of ECM1 and STAT5/p-STAT5.

Results

CLT effectively alleviated renal lesions and macrophage infiltration in IgAN mice, and improved renal function. In addition, after CLT intervention, the expression of iNOS, IL-6, TNF- α was decreased and the expression of Arg-1 was increased. ECM1 was obviously expressed in IgAN patient's renal tissue and it was negatively correlated with eGFR, while positively correlated with 24-hour proteinuria. ECM1 was also highly expressed in IgAN mice and in M1 macrophage models. In the M1 macrophage model with overexpression of ECM1, CLT inhibits macrophage M1 polarization and the production of inflammatory factors by downregulating the ECM1/STAT5 pathway.

Conclusion

CLT can effectively alleviate IgAN renal inflammatory damage, inhibit macrophage M1 polarization, and reduce the production of inflammatory factors. ECM1 was obviously expressed in IgAN renal macrophages, and the increase in ECM1 expression is related to the severity of clinical indicators in IgAN patients. The therapeutic effect of CLT on IgAN may be related to its inhibition of macrophage ECM1/STAT5 pathway.

Funding

  • Other NIH Support