Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice

Emerging evidence suggests that transforming growth factor-beta (TGF-beta) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody (alpha T) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of th e renal TGF-beta system mediates the functional and structural changes of t he more advanced stages of nephropathy, we tested whether chronic administr ation of alpha T prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. D iabetic db/db mice and nondiabetic db/m littermates were treated intraperit oneally with alpha T or control IgG, 300 mu g three times per week for 8 wk , Treatment with alpha T, but not with IgG, significantly decreased the pla sma TGF-beta 1 concentration without decreasing the plasma glucose concentr ation. The IgG-treated db/db mice developed albuminuria, renal insufficienc y, and glomerular mesangial matrix expansion associated with increased rena l mRNAs encoding alpha 1(IV) collagen and fibronectin, On the other hand, t reatment with alpha T completely prevented the increase in plasma creatinin e concentration, the decrease in urinary creatinine clearance, and the expa nsion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factore d for creatinine clearance was not significantly affected by alpha T treatm ent. We conclude that chronic inhibition of the biologic actions of TGF-bet a with a neutralizing monoclonal antibody in db/db mice prevents the glomer ulosclerosis and renal insufficiency resulting from type 2 diabetes.