Renoprotective effect of COMP- angiopoietin-1 in db/db mice with type 2 diabetes.
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-beta1 ( TGF-beta1), 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-kappaB (NF-kappaB) expression. COMP- Ang1- mediated inhibition of increased NF-kappaB-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.[1]References
- Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes. Lee, S., Kim, W., Moon, S.O., Sung, M.J., Kim, D.H., Kang, K.P., Jang, K.Y., Lee, S.Y., Park, B.H., Koh, G.Y., Park, S.K. Nephrol. Dial. Transplant. (2007) [Pubmed]
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