Ischemia followed by reperfusion induces microvascular endothelial cell injury, leading to the loss of functions such as regulation of vascular tone, tissue perfusion, permeability, and inflammation in kidney. Improvement of this endothelial dysfunction could be a good approach to treating ischemia-reperfusion-induced renal injury. Cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) is a variant of native angiogenic factor angiopoietin-1 engineered to have higher activity. We evaluated the protective effect of COMP-Ang1 in an ischemia-reperfusion renal injury model. COMP-Ang1 preserved renal peritubular capillaries after ischemia-reperfusion injury without recruiting pericytes. Pretreatment with COMP-Ang1 attenuated the increase of blood urea nitrogen and serum creatinine levels after ischemia-reperfusion. In addition, the morphological examination indicated less tubular injury in mice pretreated with COMP-Ang1 than in those treated with the vehicle. COMP-Ang1 treatment reduced the increase in the number of Gr-1-positive neutrophils or ER-HR3-positive macrophages infiltrating kidneys, increased phosphorylation of Akt, and preserved renal tissue perfusion flow and microvascular permeability. Furthermore, COMP-Ang1 decreased renal interstitial fibrosis 30 days after the ischemia-reperfusion injury. In conclusion, COMP-Ang1 can be a possible endothelial cell-targeted therapy for preventing ischemia-reperfusion-induced acute kidney injury.