The role of ubiquitin-proteasome degradation pathway in TGF-β-Smad signaling in kidney diseases

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We investigated the levels of Smads that mediate the intracellular TGF-β signaling and the activity of ubiquitin-proteasome degradation directed to Smads in isolated glomeruli from rats with anti-thymocyte serum (ATS) nephritis, a model of mesangial proliferative glomerulonephritis, and mice kidneys receiving unilateral ureteral obstruction (UUO), a model of progressive tubulointerstitial fibrosis. We found the following results.1.Smad2 protein was decreased markedly in ATS nephritic glomeruli and UUO kidneys, while Smad2 mRNA expression did not change in the former and increased in the latter, suggesting the involvement of Smad2-specific degradation mechanism in these lesions.2.Increases in degradation of intrinsic Smad2 protein and ubiquitination activity against Smad2 were noted in ATS nephritic glomeruli and UUO kidneys, and the degradation of Smad2 was blocked by a proteasome inhibitor.3.We cloned the rat Smurf2, an E3 ubiquitin ligase for Smad2.4.Increases in Smurf2 protein and mRNA were noted in ATS nephritic glomeruli and UUO kidneys.5.The decrease of inhibitory Smad7 protein and the enhanced ubiquitination and degradation of Smad7 protein were noted in UUO kidneys, in which the expression of Smad7 mRNA increased.6.The degradation of Smad7 in UUO kidneys was inhibited by a proteasome inhibitor.These data suggest that the increase of the selective ubiquitin-dependent degradation of Smad2 mediated by Smurf2 results in relative predominance of Smad3-mediated TGF-β signaling in ATS nephritic glomeruli and UUO kidneys. The decrease of inhibitory Smad7 resulted from enhanced ubiquitin-dependent degradation may also be involved in the progression of tubulointerstitial fibrosis in UUO kidneys, in which uncontrolled overexpression of TGF-β activity plays a pathogenic role.