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      Arkadia-Smad7-Mediated Positive Regulation of TGF-β Signaling in a Rat Model of Tubulointerstitial Fibrosis

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          Background/Aims: Upregulation of transforming growth factor beta (TGF-β)/Smad signaling has been implicated in the primary pathogenesis of renal fibrosis. The ubiquitin-proteasome pathway has an important influence on TGF-β 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-β type I receptor (TβRI), principal molecules in the regulation of TGF-β signaling, to understand the regulatory mechanism of ubiquitin-proteasomal degradation of TGF-β 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, TβRI, TGF-β1, 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, TβRI, TGF-β1 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 TβRI, and Arkadia only interacted with Samd7 but not with TβRI. Conclusion: Reduction of Smad7 resulting from ubiquitin-dependent degradation may be mainly attributed to Arkadia, and Arkadia-Smad7-mediated positive regulation of TGF-β signaling may play a promoting role in the progression of tubulointerstitial fibrosis.

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          Most cited references 18

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          Transforming growth factor beta in tissue fibrosis.

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            Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.

            Smad7 is an inhibitory Smad that acts as a negative regulator of signaling by the transforming growth factor-beta (TGF-beta) superfamily proteins. Smad7 is induced by TGF-beta, stably interacts with activated TGF-beta type I receptor (TbetaR-I), and interferes with the phosphorylation of receptor-regulated Smads. Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7. These results thus reveal a novel function of Smad7, i.e. induction of degradation of TbetaR-I through recruitment of an E3 ligase to the receptor.
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              Smad7 Binds to Smurf2 to Form an E3 Ubiquitin Ligase that Targets the TGFβ Receptor for Degradation


                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                April 2007
                07 March 2007
                : 27
                : 2
                : 176-183
                Department of Nephrology, Second Xiangya Hospital of the Central South University, Changsha, China
                100518 Am J Nephrol 2007;27:176–183
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 23, Pages: 8
                Original Report: Laboratory Investigation


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