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NDT Advance Access originally published online on November 3, 2006
Nephrology Dialysis Transplantation 2007 22(2):396-408; doi:10.1093/ndt/gfl598
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes

Sik Lee1, Won Kim1, Sang-Ok Moon1, Mi Jeong Sung1, Duk Hoon Kim1, Kyung Pyo Kang1, Kyu Yoon Jang2, Sang Yong Lee3, Byung Hyun Park4, Gou Young Koh5 and Sung Kwang Park1

1Department of Internal Medicine, 2Department of Pathology, 3Department of Radiology, 4Department of Biochemistry, Renal Regeneration Laboratory, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju and 5Biomedical Research Center and Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

Correspondence and offprint requests to: Sung Kwang Park, MD, Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju, 561-712, Republic of Korea. Email: parksk{at}chonbuk.ac.kr



  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-ß1 (TGF-ß1), {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-{kappa}B (NF-{kappa}B) expression. COMP-Ang1-mediated inhibition of increased NF-{kappa}B-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.

Conclusion. We conclude that COMP-Ang1 delayed the fibrotic changes in the kidney of diabetic db/db mice through its anti-inflammatory or metabolic effects.

Keywords: COMP-angiopoietin-1; diabetic db/db mouse; inflammation; kidney


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