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Abstract: TH-PO106

Remote Ischemic Preconditioning Confers Renoprotection Against Septic AKI via Exosomal miR-21

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Pan, Tianyi, zhongshan hospital affiliated to Fudan University, Shanghai, China

Group or Team Name

  • AKI
Background

Renal ischemic preconditioning is beneficial for multiple organs in response to ischemic injury. Whether limb remote ischemia preconditioning (limb rIPC) functions as a protective effector against sepsis-associated AKI is unclear, and the underlying mechanism has not been fully elucidated.Our study aimed to explore the protective role of limb rIPC in mice with AKI induced bycecal ligation and puncture (CLP).

Methods

In vivo, we preconditioned CLP-challenged mice with remote ischemia and reperfusion in the bilateral femoral arteries, which were subjected to 4 cycles of clamping for 5 minutes and unclamping for 5 minutes. Organ function and indicators of inflammation and apoptosis were examined, and the potential mechanism was determined. In vitro, we extracted myocyte-derived exosomes under hypoxia and re-oxygen preprocessing, and these exosomes were pre-added to lipopolysaccharide (LPS)-treated mouse tubular epithelial cells (mTECs).

Results

In vivo, limb rIPC protected polymicrobial septic mice from multiple organ dysfunction and morphological damage, via anti-inflammatory and anti-apoptotic effects. However, limb rIPC could not attenuate CLP-induced renal injury in miR-21 knockout mice. rIPC enhanced local miR-21 expression in ischemic limbs in a hif-1α dependent way, and miR-21 expression in serum exosomes and remote organs, such as the kidney and lung, was up-regulated. This beneficial effector was potentially transmitted in circulation by exosomal transfer. Meanwhile, an elevation in miR-21 was detected in exosomes derived from myocytes with hypoxia and re-oxygen pretreatment. The exosomal preconditioning resulted in renal protection and a reduction in inflammatory cytokines and in mTEC apoptosis in response to septic injury. We further found that high miR-21 expression inhibited miR-21 target genes, exerting anti-inflammation and anti-apoptosis effects.

Conclusion

Enhanced exosomal miR-21 that is induced by limb remote ischemia preconditioning contributes to renoprotection against sepsis. Our data suggest a novel and promising therapeutic strategy for septic AKI.

Funding

  • Government Support - Non-U.S.