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Abstract: SU-OR10

Endothelial-Derived miR-17~92 Promotes Angiogenesis to Protect Against Renal Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Chiba, Takuto, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
  • Ho, Jacqueline, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
Background

Acute kidney injury (AKI), resulting from renal ischemia reperfusion injury (IRI) among others, is an independent predictor of morbidity and mortality, and is identified in as many as 50% of ICU patients. Damage to the renal microvasculature is a hallmark of renal IRI. miR-17~92 encodes 6 polycistronic microRNAs that show potent pro-angiogenic capacity by targeting anti-angiogenic factors. The function of miR-17~92 in renal microvasculature after renal IRI remains unknown.

Methods

Antibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17~92 knockout (miR-17~92endo-/-) mice were generated and a renal IRI model was performed. Mice were monitored for the development of AKI using serum chemistries and tissue analysis, and for renal blood flow using a magnetic resonance imaging (MRI). Mice were treated with miRNA mimics during renal IRI to test its therapeutic efficacies.

Results

we demonstrate that miRs-17, -18a, -20a, and -19b are up-regulated in renal endothelial cells after renal IRI in mice. miR-17~92endo-/- exacerbates ischemic AKI in male and female mice. Specifically, miR-17~92endo-/- promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress and promotes macrophage infiltration to injured kidneys. The potent anti-angiogenic factor, thrombospondin 1 (TSP1), is highly expressed in renal endothelium in miR-17~92endo-/- after renal IRI and is a target of miR-18a and miR-19a/b. Beyond defining a critical role for miR-17~92 in the angiogenic response after ischemic AKI, we show that co-treatment with a combination of miR-18a and miR-19b mimics is sufficient to mitigate ischemic AKI.

Conclusion

These data suggest that endothelial-derived miR-17~92 stimulates a reparative response in damaged renal vasculature during ischemic AKI by regulating angiogenic pathways.

Funding

  • NIDDK Support