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Background Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of acute kidney injury reported during the COVID-19 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The micro-RNA miR-218-5p is upregulated in endothelial progenitor cells following hypoxia, but miRNA regulation of Tie2 in the endothelial progenitor cell (EPC) lineage is unclear. Methods We isolated EPCs derived from the human kidney (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. Results Following ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-loxP mammalian model—a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309+ cells, homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. Conclusions These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.