Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney.
Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney.
Hill
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C
Department of Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TH, UK.
Flyvbjerg
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A
Rasch
R
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Bak
M
M
Logan
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D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology; D009929:Organ Size; D010446:Peptide Fragments / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology*; D053781:Transforming Growth Factor beta2
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D011347:Procollagen; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; C042813:procollagen type I carboxy terminal peptide