title: Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice.
abstract: BACKGROUND
  Peritubular capillary injury induces chronic hypoxia in the renal tubulointerstitium, and renal peritubular capillary dysfunction is an early event that contributes to tubulointerstitial fibrosis. Cyclosporine A (CsA) is a potent immunosuppressant and improves survival of renal allografts. However, the limitation of CsA use is chronic nephrotoxicity. A soluble, stable and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1 has been developed. We investigated whether COMP-Ang1 ameliorates CsA-induced renal injury.
  
  
  METHODS
  CsA-treated mice were injected with recombinant adenovirus expressing either COMP-Ang1 or LacZ. Histology, inflammatory, haemodynamic and fibrotic parameters, and signalling pathway were evaluated.
  
  
  RESULTS
  Histologic examination showed that COMP-Ang1 significantly decreased CsA-induced tubular damage and tubulointerstitial fibrosis. CsA-induced increases in macrophage infiltration and expression of MCP-1 and ICAM-1 after CsA treatment were significantly reduced by COMP-Ang1. Treatment with COMP-Ang1 also decreased the CsA-induced increases in TGF-beta1 and Smad 2/3 levels while increasing Smad 7 levels. Laser-Doppler sonographic findings and endothelial factor VIII staining revealed that COMP-Ang1 preserved the integrity of peritubular vasculature and intrarenal haemodynamics from the CsA-induced renal injury. COMP-Ang1 inhibited tubular cell apoptosis while increasing tubular cell proliferation in CsA-induced renal injury.
  
  
  CONCLUSIONS
  These results indicate that COMP-Ang1 exhibited a protective effect on damaged peritubular capillaries, haemodynamic alteration and inflammation in CsA-induced renal injury. Thus, COMP-Ang1 may be useful as a therapeutic and prophylactic agent for specific protection against endothelial dysfunction and inflammation.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju, 561-712, Korea.
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.forename: Duk Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Sang-Ok
authors.initials: SO
authors.lastname: Moon
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: Ae Sin
authors.initials: AS
authors.lastname: Lee
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Sung
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects*; D007674:Kidney Diseases / Q000188:drug therapy*; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008833:Microcirculation / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism
chemical_list: C515576:COMP-Ang1 fusion protein; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; 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; C508645:monocyte chemoattractant protein 1 (66-77); D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine