Arkadia-Smad7-mediated positive regulation of TGF-beta signaling in a rat model of tubulointerstitial fibrosis

Background/Aims: Upregulation of transforming growth factor beta (TGF-beta)/Smad signaling has been implicated in the primary pathogenesis of renal fibrosis. The ubiquitin-proteasome pathway has an important influence on TGF-beta signaling through regulating Smad degradation. As E3 ubiquitin ligases, both Arkadia and Smurf2 are involved in this prosess. In this study, we focused on Arkadia, Smurf2, Smad7, and TGF-beta type I receptor (T beta RI), principal molecules in the regulation of TGF-beta signaling, to understand the regulatory mechanism of ubiquitin-proteasomal degradation of TGF-beta signaling in the pathogenesis of renal fibrosis. Methods: A unilateral ureteral obstruction (UUO) model was employed, and sham-operated rats were used as controls. Renal lesions and the expression of Arkadia, Smurf2, Smad7, T beta RI, TGF-beta 1, and type 1 collagen (COL-1) were detected by Western blot, immunoprecipitation, immunohistochemistry, and/or reverse transcription-polymerase chain reaction. Results: The results indicated progressive tubulointerstitial fibrosis, high expression levels of Arkadia, Smurf2, T beta RI, TGF-beta 1 mRNA, type 1 collagen mRNA, and Smad7 mRNA, and low levels of Smad7 protein in the kidneys of rats with unilateral ureteral obstruction, in which Smurf2 interacted with both Smad7 and T beta RI, and Arkadia only interacted with Samd7 but not with T beta RI. Conclusion: Reduction of Smad7 resulting from ubiquitin-dependent degradation may be mainly attributed to Arkadia, and Arkadia-Smad7-mediated positive regulation of TGF-beta signaling may play a promoting role in the progression of tubulointerstitial fibrosis. Copyright (c) 2007 S. Karger AG, Basel