Journal
NEPHROLOGY
Volume 16, Issue 1, Pages 76-86Publisher
WILEY
DOI: 10.1111/j.1440-1797.2010.01367.x
Keywords
myofibroblasts; renal fibroblasts; transforming growth factor-beta; ubiquitin proteasome system; unilateral ureteral obstruction
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Aim: Transforming growth factor-beta (TGF-beta) is involved in renal tubulointerstitial fibrosis. Recently, the ubiquitin proteasome system was shown to participate in the TGF-beta signalling pathway. The aim of this study was to examine the effects of proteasome inhibitors on TGF-beta-induced transformation of renal fibroblasts and tubular epithelial cells in vitro and on unilateral ureteral obstruction (UUO) in vivo. Methods: Rat renal fibroblasts NRK-49F cells and tubular epithelial cells, NRK-52E, were treated with TGF-beta in the presence or absence of a proteasome inhibitor, MG132 or lactacystin. Rats were subjected to UUO and received MG132 i.p. for 7 days. Results: In cultured renal cells, both MG132 and lactacystin inhibited TGF-beta-induced alpha-smooth muscle actin (alpha-SMA) protein expression according to both western blotting and immunofluorescent study results. MG132 also suppressed TGF-beta-induced mRNA expression of alpha-SMA and upregulation of Smad-response element reporter activity. However, MG132 did not inhibit TGF-beta-induced phosphorylation and nuclear translocation of Smad2. In contrast, MG132 increased the protein level of Smad co-repressor SnoN, demonstrating that SnoN is one of the target molecules by which MG132 blocks the TGF-beta signalling pathway. Although the proteasome inhibitor suppressed TGF-beta-induced transformation of cultured fibroblasts and tubular epithelial cells, MG132 treatment did not ameliorate tubulointerstitial fibrosis in the rat UUO model. Conclusion: Proteasome inhibitors attenuate TGF-beta signalling by blocking Smad signal transduction in vitro, but do not inhibit renal interstitial fibrosis in vivo.
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