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Abstract: SA-OR013

Tubular HIF-1α Activates Macrophages via Exosomal MicroRNA-23a to Promote Tubulointerstitial Inflammation

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Zuolin, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
  • Lv, Linli, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
  • Ji, Jialing, Nanjing Medical University, Nanjing, China
  • Feng, Ye, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
  • Liu, Bi-Cheng, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
Background

Hypoxia is a key instigator of tubulointerstitial inflammation (TI) which has been assumed related with hypoxia inducible factor-1 (HIF-1), a master regulator response to hypoxia. While the exact mechanism of HIF-1 on this pathophysiological process is still largely unclear.

Methods

Hypoxia-related TI was induced in I/R injury and UUO models. Exosomes from hypoxic kidney and hypoxic TECs were isolated. The role of HIF-1 on miR-23a expression was studied using CHIP-PCR. Besides, exosomal miR-23a was inhibited or overexpressed to explore its functional role in macrophage. In vivo, TECs exosomes overexpressed or silenced miR-23a was transferred to mice via kidney parenchyma injection. Furthermore, treatment of miR-23a inhibitor in I/R model was also performed.

Results

TI was highly associated with the time-course expression of tubular HIF-1α in I/R injury and UUO mice. Meanwhile, the kidney exosomal miR-23a was markedly increased. In vitro, hypoxic TECs presented with higher HIF-1α and upregulation of NF-κB as well as exosomal miR-23a. HIF-1α could transcriptionally regulate miR-23a in exosomes. Exosome from hypoxic TECs could develop more severe macrophage activation compared to exosome from normal TECs. Furthermore, we demonstrated that exosomal miR-23a directly suppressed its target A20, leading to macrophage activation. Inhibition of miR-23a reversed macrophage activation. In vivo, TI was significantly increased when mice transferred with miR-23a enriched exosomes, which was not shown by miR-23a silenced exosomes. Furthermore, treatment of miR-23a inhibitor in I/R model could ameliorate TI significantly.

Conclusion

Our study firstly demonstrates that tubular HIF-1 regulated macrophage function via exosomal miR-23a to promote hypoxia-related TI. The finding provides a novel strategy to target HIF1α-miR-23a axis in preventing hypoxia induced kidney injury.

Funding

  • Government Support - Non-U.S.