title: COMP-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model.
abstract: Injury to the renal microvasculature may be a major factor in the progression of renal disease; therefore, protection of endothelial cells (EC) in renal vasculature may have a therapeutic role in renal fibrosis. Recently, a soluble, stable, and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, was developed. The contribution of COMP-Ang1 in renal interstitial fibrosis, however, remains to be clarified. This study investigated the effects of COMP-Ang1 on peritubular capillary EC in the renal cortex and the renal fibrogenic process that is triggered by unilateral ureteral obstruction. COMP-Ang1 preserved renal platelet-EC adhesion molecule-1-and Tie2-positive EC. Morphologic examination indicated less tubular injury and tubulointerstitial fibrosis in mice that received COMP-Ang1 than vehicle-treated mice. Interstitial type I collagen and myofibroblast accumulation were significantly suppressed by COMP-Ang1 treatment. COMP-Ang1 increased Tie2 and Akt phosphorylation in ureteral obstructed kidneys. Renal surface microvasculature and renal blood flow were higher after treatment with COMP-Ang1 than with vehicle. COMP-Ang1 treatment decreased monocyte/macrophage infiltration, tissue levels of TGF-beta1, and Smad 2/3 phosphorylation and increased Smad 7 in the obstructed kidney. These results demonstrate that COMP-Ang1 treatment can decrease the progression of renal fibrosis in unilateral ureteral obstruction. COMP-Ang1 may be an endothelium-specific therapeutic modality in fibrotic renal disease.
authors.affiliation: Renal Regeneration Laboratory and Department of Internal Medicine, Chonbuk National University Medical School, San 2-20 Keumam-dong, Jeonju, 561-180, South Korea.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.forename: Sang-Ok
authors.initials: SO
authors.lastname: Moon
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Chung-Hyun
authors.initials: CH
authors.lastname: Cho
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Kyu-Sil
authors.initials: KS
authors.lastname: Choi
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Sung
authors.forename: Duk Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
mesh_terms: D042683:Angiopoietin-1 / Q000627:therapeutic use*; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000627:therapeutic use*; D005355:Fibrosis; D006023:Glycoproteins / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D008297:Male; D064235:Matrilin Proteins; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012077:Renal Artery; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy*
chemical_list: D042683:Angiopoietin-1; D000943:Antigens, Differentiation; C515576:COMP-Ang1 fusion protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D053773:Transforming Growth Factor beta1; C036763:monocyte-macrophage differentiation antigen; D042787:Receptor, TIE-2; D051057:Proto-Oncogene Proteins c-akt