Journal Article

Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice

Sik Lee, Won Kim, Duk Hoon Kim, Sang-Ok Moon, Yu Jin Jung, Ae Sin Lee, Kyung Pyo Kang, Kyu Yun Jang, Sang Yong Lee, Mi Jeong Sung, Gou Young Koh and Sung Kwang Park

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 23, issue 9, pages 2784-2794
Published in print September 2008 | ISSN: 0931-0509
Published online May 2008 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfn168
Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice

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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-β1 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.

Keywords: COMP-angiopoietin-1; cyclosporine A; endothelial cells; renal fibrosis

Journal Article.  5009 words.  Illustrated.

Subjects: Nephrology

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