NDT Advance Access originally published online on May 7, 2008
Nephrology Dialysis Transplantation 2008 23(9):2784-2794; doi:10.1093/ndt/gfn168
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Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice
1 Department of Internal Medicine 2 Pathology 3 Radiology, Renal Regeneration Laboratory, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju 4 Food Function Research Division, Korea Food Research Institute, Sungnam 5 Biomedical Research Center and Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon, Korea
Correspondence and offprint requests to: Sung Kwang Park, Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju, 561-712, Korea. Tel: +82-63-250-1683; Fax: +82-63-254-1609; E-mail: parksk{at}chonbuk.ac.kr
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Abstract |
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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
Received for publication: 3. 8.07
Accepted in revised form: 4. 3.08
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  Y. J. Jung, D. H. Kim, A. S. Lee, S. Lee, K. P. Kang, S. Y. Lee, K. Y. Jang, M. J. Sung, S. K. Park, and W. Kim Peritubular capillary preservation with COMP-angiopoietin-1 decreases ischemia-reperfusion-induced acute kidney injury Am J Physiol Renal Physiol, October 1, 2009; 297(4): F952 - F960. [Abstract] [Full Text] [PDF]
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