Activation of the Smad pathway in glomeruli from a spontaneously diabetic rat model, OLETF rats

Background/Aims: Transforming growth factor-beta (TGF-beta) mediates the excess accumulation of extracellular matrix in the diabetic kidney. Smad family proteins have been identified as signal transducers for the TGF-beta superfamily. We sought to characterize the role of Smad proteins in mediating TGF-beta responses in the development of diabetic nephropathy. Methods: We evaluated the time course of TGF-beta(1) fibronectin, Smad2 and Smad3 protein expression and Smad3 activation in glomeruli from spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using immunohistochemistry and Western blot analysis. Results: The glomeruli of diabetic OLETF rats showed not only accelerated activation of Smad3, but also enhanced protein expression of Smad2 and Smad3, which occurred in parallel to the increased expression of TGF-beta and fibronectin compared with glomeruli of control, Long-Evans Tokushima Otsuka (LETO) rats at 30 weeks of age. No differences were found in TGF-beta(1) fibronectin, Smad2 and Smad3 protein expression and Smad3 activation in glomeruli between the two strains at 12 weeks of age when OLETF rats were not diabetic. Conclusions: The enhancement of Smad protein expression and activation may be involved in the TGF-beta signaling cascade that plays an important role in the development of diabetic nephropathy through progressive expansion of the mesangial matrix. Copyright (C) 2004 S. Karger AG, Basel.