Transforming growth factor-beta 2 antibody attenuates fibrosis in the experimental diabetic rat kidney

Diabetic nephropathy is characterised by an increase in glomerular and tubu lar fibrosis that compromises kidney function. The transforming growth fact or-betas (TGF-betas) have been shown to play a major role in fibrosis and w e have shown that TGF-beta2, in particular, increases coordinately with fib rogenesis 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 mo noclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were s plit into two groups. The first were treated with 5 mg/kg irrelevant contro l IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recom binant monoclonal anti-TGF-beta2 IgG4 (termed CAT-132) systemically every s econd day for 14 days. A further group of six non-diabetic rats was also us ed as a control. Various biological parameters were measured daily througho ut the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-prop eptide, which is an indicator of the rate of collagen-I synthesis,within th e kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urin ary albumin excretion (UAE) and kidney weights were all significantly highe r 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 inc rease in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibroge nesis. 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-T GF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats . We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-be ta2 antibody, during the acute stages of diabetic nephropathy reduces the r ate of pathogenic fibrosis in the kidney.