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.


CONCLUSIONS
We conclude that COMP-Ang1 delayed the fibrotic changes in the kidney of diabetic db/db mice through its anti-inflammatory or metabolic effects.
Lee
Sik
S
Department of Internal Medicine, Chonbuk National University Medical School, 634-18 Keum-Am Dong, Jeonju 561-712, Republic of Korea.
Kim
Won
W
Moon
Sang-Ok
SO
Sung
Mi Jeong
MJ
Kim
Duk Hoon
DH
Kang
Kyung Pyo
KP
Jang
Kyu Yoon
KY
Lee
Sang Yong
SY
Park
Byung Hyun
BH
Koh
Gou Young
GY
Park
Sung Kwang
SK
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000096:biosynthesis; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D016896:Treatment Outcome
D001786:Blood Glucose; C515576:COMP-Ang1 fusion protein; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1