Cell proliferation, matrix production, and Smad-mediated intracellular TGF-β signaling in glomerulonephritis

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We investigated the changes of Smad-mediated intracellular TGF-β signaling in glomeruli of rats with anti-thymocyte serum (ATS) nephritis, in which glomeruli show transient increase of TGF-β1 expression and matrix deposition, and found the following results.1. Smad2 protein decreased markedly in ATS nephritic glomeruli, while no significant changes were noted in the levels of Smad3 and Smad4 proteins.2. No significant changes were noted in glomerular expression of Smad2 mRNA, suggesting that the decrease of Smad2 protein was not due to decreased gene expression, but to regulated degradation of Smad2 protein.3. Degradation of endogenous Smad2 protein increased remarkably in ATS nephritic glomeruli.4. Ubiquitination of exogenous recombinant Smad2 increased in the glomerular extracts obtained from rats with ATS nephritis.5. Expression of Smurf2, an E3 ubiquitin ligase for Smad2, increased in ATS nephritic glomeruli.6. The number of glomerular nuclei positive for Smad3 increased in ATS nephritic glomeruli, suggesting that Smad3-mediated TGF-β signaling worked in ATS nephritic glomeruli.These data suggest that the decrease of Smad2 resulted from enhanced ubiquitin-dependent degradation of Smad2 mediated by Smurf2 is involved in the regulation of Smad2-mediated TGF-β signaling in ATS nephritic glomeruli. Increase of the selective degradation of Smad2 may cause relative predominance of Smad3-mediated TGF-β signaling in ATS nephritic glomeruli.