Endothelial-Derived Mir-17 Similar To 92 Promotes Angiogenesis To Protect Against Renal Ischemia-Reperfusion Injury

Background Damage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)-mediated AKI. The miR-17 similar to 92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established. Methods Antibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17 similar to 92 knockout (miR-17 similar to 92(endo-/-)) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated. Results miR-17, -18a, -20a, -19b, and pri-miR-17 similar to 92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17 similar to 92(endo-/-) exacerbates renal IRI in male and female mice. Specifically, miR-17 similar to 92(endo-/-) promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17 similar to 92(endo-/-) after renal IRI and is a target of miR-18a and miR-19a/b. miR-17 similar to 92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate. Conclusions These data suggest that endothelial-derived miR-17 similar to 92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.Significance Statement Regulation of endothelial cells is important in many biologic processes, including development, organ function, and disease. The kidney vasculature is highly sensitive to hypoxic injury and has a limited capacity for repair. AKI as a result of decreased blood flow is common, and there are no current therapies. MicroRNAs are small noncoding RNAs that inhibit expression of target genes. Endothelial-derived miR-17 similar to 92 is a cluster of microRNAs critical for endothelial function and repair during AKI in mice. Furthermore, pharmacologic treatment with mimics of the cluster mitigates AKI, promoting angiogenesis. These microRNAs are the first potential therapeutic target for kidney endothelial damage after AKI, and mimics may be broadly applicable to disease processes that involve endothelial injury.