Injury to the renal microvasculature and inflammatory process may be major factors in the progression of renal disease, therefore, protection of the renal endothelial cell and regulation of inflammatory process may be an important therapeutic target of renal disease. Thus, we evaluated the protective effect of cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) in unilateral ureteral obstruction (UUO)-induced renal fibrosis, cyclosporine A (CsA)-induced renal injury, and the diabetic nephropathy model. In the UUO model, morphologic examination indicated less tubular injury and tubulointerstitial fibrosis in mice that received COMP-Ang1 compared to vehicle-treated mice. Interstitial type I collagen, myofibroblast accumulation, renal surface microvasculature and renal blood flow were higher after treatment with COMP-Ang1 compared to vehicle-treated mice. COMP-Ang1 treatment decreased monocyte/macrophage infiltration, tissue levels of transforming growth factor beta1, and Smad 2/3 phosphorylation and increased Smad 7 in the obstructed kidney. In CsA-induced renal injury, histologic examination showed significantly decreased CsA- induced tubular damage and tubulointerstitial fibrosis in COMP-Ang1 treated mice. COMP-Ang1 administration also decreased increased macrophage infiltration, adhesion molecule expression, TGF-beta1, and Smad 2/3 levels in CsA-treated kidneys, while increasing Smad 7 levels. Laser-Doppler sonographic findings and endothelial factor VIII staining revealed that COMP-Ang1 had a preservative effect on peritubular vasculature. In the diabetic nephropathy model, COMP-Ang1 reduced albuminuria and decreased mesangial expansion, thickening of the glomerular basement membrane and podocyte foot process broadening and effacement. COMP-Ang1 may delay the fibrotic changes in the kidney of diabetic db/db mice through its anti- inflammatory or metabolic effects. In conclusion, COMP-Ang1 may be an endothelium-specific and anti- inflammatory therapeutic modality in fibrotic renal disease.