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Abstract: FR-OR055

Macrophage-Derived Migrasomes Transfer of IL-11 Is a Novel Mechanism of Renal Interstitial Fibrosis in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhu, Xiaodong, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Zhao, Yu, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Jiang, Yuteng, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Liu, Yuqiu, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Zhang, Xiaoliang, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
Background

Migrasome is a newly discovered, migration-dependent vesicle which differ dramatically from common extracellular vesicles(EVs) and primarily aid in intercellular communications. Macrophages infiltration and fibroblasts activation have been closely associated with renal interstitial fibrosis in diabetic nephropathy(DN). Whether macrophage produce migrasomes and contribute to the pathological processes are unknown.

Methods

Macrophage migrasomes were examined in streptozotocin murine model and Raw264.7 cells by transmission/scanning electron microscopy. Migrasomes isolated from M1/M2 phenotype macrophage, high glucose treated macrophage (M1-mig, M2-mig, HG-mig)interaction with renal fibroblast were assessed and migrasome gene profiling to identify the intercellular signaling.

Results

Ultrastructural analysis revealed that macrophage produce the previously unrecognized vesicles (Fig1.arrowhead) that typically grow on the tips or intersections of retraction fibers(Fig1.triangle). The vesicles were confirmed as the newly discovered migrasome by morphology and biomarker data that distinguish them from common EVs. We noticed that activated macrophage and HG enhanced migrasome production. Released migrasomes can directly initiate fibroblasts transdifferentiation which fibrosis markers (αSMA, COL1) markedly increased in HG/M1-mig group (by 10-15fold, respectively), while migrasome inhibitor CK636 or Dynasore alleviate fibrosis in DN model. We performed migrasomes gene-profiling to determine what intercellular fibrosis messages might be delivering. Amongst the top ranking genes, notably, we found a specific enrichment of IL-11 mRNA in HG-mig and M1-mig. The knockout IL-11 migrasomes or blocking fibroblasts IL-11RA sharply decreased the fibrosis levels.

Conclusion

Our findings suggest a fundamental, but formerly unrecognized pattern via which macrophage exert their effects through migrasomes and more depth of their functional roles shall be unearthed. IL-11 in HG/M1-mig driving fibroblasts transdifferentiation may be a novel mechanism of fibrosis in DN.

Funding

  • Government Support - Non-U.S.