Kidney Week

Abstract: SA-OR013

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

Session Information

• AKI: Inflammation and Regeneration
  October 27, 2018 | Location: 6B, San Diego Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Li, Zuolin, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China

Zuolin Li, PhD



Zuolin Li, PhD candidate Mr Li received his Medical Degree in 2014, Master Degree in nephrology in 2016 at Qingdao University, China. Now he is studying in nephrology at Southeast University. His major research interest is focusing on HIF signaling in acute and chronic kidney. He published 5 publications.

• Lv, Linli, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China

Linli Lv,

• Ji, Jialing, Nanjing Medical University, Nanjing, China

Jialing Ji,

• Feng, Ye, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China

Ye Feng,

• Liu, Bi-Cheng, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China

Bi-Cheng Liu,

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.