Transforming growth factor-beta (TGF-beta) is known to promote the accumulation of extracellular matrix (ECM) and the development of diabetic nephropathy. Halofuginone, ail analog of febrifugine, has been shown to block TGF-beta(1) signaling and Subsequent type 1 collagen Production. Here, the inhibitory effect of halofuginone on diabetic nephropathy was examined. Halofuginone Suppressed Smad2 phosphorylation induced by TGF-beta(1) in Cultured mesangial cells. In addition, the expression of TGF-beta type 2 receptor decreased by halofuginone. Halofuginone showed ail inhibitory effect oil type 1 collagen and fibronectin expression promoted by TGF-beta(1). Ail in vivo experiment using db/db mice confirmed the ability of halofugirione to suppress mesangial expansion and Fibronectin overexpression in the kidneys. Moreover, an analysis of urinary 8-OHdG level and dihydroethidium fluorescence revealed that halofuginone reduced oxidative stress in the glomerulus of db/db mice. These data indicate that halofuginone prevents ECM deposition and decreases oxidative stress, thereby suppressing the progression of diabetic nephropathy. (c) 2008 Elsevier Inc. Ail rights reserved.