Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice.
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.
Lee
Sik
S
Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju, 561-712, Korea.
Kim
Won
W
Kim
Duk Hoon
DH
Moon
Sang-Ok
SO
Jung
Yu Jin
YJ
Lee
Ae Sin
AS
Kang
Kyung Pyo
KP
Jang
Kyu Yun
KY
Lee
Sang Yong
SY
Sung
Mi Jeong
MJ
Koh
Gou Young
GY
Park
Sung Kwang
SK
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
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