title: Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes.
abstract: BACKGROUND
  Inflammatory processes have been recently seen as underlying the pathogenesis of diabetic nephropathy. Angiopoietin-1 (Ang1) plays essential roles in regulating vascular growth, development, maturation, permeability and inflammation. We have developed a soluble, stable and potent Ang1 variant, cartilage oligomeric matrix protein (COMP)-Ang1.
  
  
  METHODS
  In this study, db/db mice were treated with recombinant adenovirus expressing either COMP-Ang1 or LacZ. Histology, inflammatory, metabolic, and fibrotic parameters and signalling pathway were evaluated.
  
  
  RESULTS
  COMP-Ang1 reduced albuminuria and decreased mesangial expansion, thickening of the glomerular basement membrane and podocyte foot process broadening and effacement. COMP-Ang1 suppressed both renal expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 and monocyte/macrophage infiltration in diabetic db/db mice. COMP-Ang1 also reduced renal tissue levels of transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin, fibronectin, as well as Smad 2/3 expression, but increased Smad 7 expression. In human umbilical vein endothelial cells (HUVECs) grown in high glucose concentrations of glucose, recombinant COMP-Ang1 protein decreased nuclear factor-kappaB (NF-kappaB) expression. COMP-Ang1-mediated inhibition of increased NF-kappaB-DNA binding in nuclear extracts from HUVECs grown in high glucose was significantly blocked by soluble Tie2 receptor-Fc. In addition, COMP-Ang1 significantly decreased fasting blood glucose level, epididymal fat weight to body weight ratio, and epididymal adipocyte size in diabetic db/db mice. After intraperitoneal glucose challenge, COMP-Ang1 significantly lowered plasma glucose levels. However, there was no difference in serum insulin levels.
  
  
  CONCLUSIONS
  We conclude that COMP-Ang1 delayed the fibrotic changes in the kidney of diabetic db/db mice through its anti-inflammatory or metabolic effects.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, 634-18 Keum-Am Dong, Jeonju 561-712, Republic of Korea.
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.forename: Sang-Ok
authors.initials: SO
authors.lastname: Moon
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Sung
authors.forename: Duk Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
authors.forename: Kyu Yoon
authors.initials: KY
authors.lastname: Jang
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Byung Hyun
authors.initials: BH
authors.lastname: Park
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000096:biosynthesis; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; C515576:COMP-Ang1 fusion protein; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1