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Kidney Week

Abstract: FR-PO053

miR-146a Targeted to Splenic Macrophages Prevents Sepsis-Induced Multiple Organ Injury Including AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Funahashi, Yoshio, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Kato, Noritoshi, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Tsuboi, Naotake, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Nagoya, Japan

Group or Team Name

  • Department of Nephrology
Background

To date, additional pathophysiology and new drug concept need to be provided in patients with multiple organ injury due to sepsis. microRNAs (miRNAs) have garnered attention as potent oligonucleotide therapeutics. The aim of the present study is to investigate the pathophysiological role of exogenous miR-146a in sepsis-induced acute kidney injury (AKI).

Methods

In vitro study, RAW264.7 cells were transfected with miR-16, miR-126, miR-146a, miR-200b, or a negative control, then treated with 1 mg/ml lipopolysaccharide (LPS) for 6 hours. In vivo study, young C57BL/6 mice were intravenously injected a mixture of miR-146a-expressing plasmid and polyethyleneimine (PEI). 7 days after transfection, sepsis was induced via cecal ligation and puncture (CLP).

Results

Among tested miRNA, miR-146a showed the best suppressive efficacy, whereby transcriptional activity of NF-κB was decreased by targeting IRAK-1 and TRAF6 in RAW264.7 cells. Treatment with the miR-146a-expressing plasmid/PEI complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury including kidney injury, and led to increased survival in CLP-induced polymicrobial sepsis. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages, but not in kidney cells. The miR-146a-treated CLP mice also showed a significant decrease in NF-κB activation and apoptosis in splenocytes. Splenectomy diminished the anti-inflammatory effects of miR-146a.

Conclusion

The induction of miR-146a in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury, including AKI. This study provides a pathophysiological breakthrough in the relationship between splenic macrophages and sepsis-induced AKI.