benzyloxycarbonylleucyl-leucyl-leucine-aldehyde and Ureteral-Obstruction

Transforming growth factor-β (TGF-β) is involved in renal tubulointerstitial fibrosis. Recently, the ubiquitin proteasome system was shown to participate in the TGF-β signalling pathway. The aim of this study was to examine the effects of proteasome inhibitors on TGF-β-induced transformation of renal fibroblasts and tubular epithelial cells in vitro and on unilateral ureteral obstruction (UUO) in vivo.. Rat renal fibroblasts NRK-49F cells and tubular epithelial cells, NRK-52E, were treated with TGF-β 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.. In cultured renal cells, both MG132 and lactacystin inhibited TGF-β-induced α-smooth muscle actin (α-SMA) protein expression according to both western blotting and immunofluorescent study results. MG132 also suppressed TGF-β-induced mRNA expression of α-SMA and upregulation of Smad-response element reporter activity. However, MG132 did not inhibit TGF-β-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-β signalling pathway. Although the proteasome inhibitor suppressed TGF-β-induced transformation of cultured fibroblasts and tubular epithelial cells, MG132 treatment did not ameliorate tubulointerstitial fibrosis in the rat UUO model.. Proteasome inhibitors attenuate TGF-β signalling by blocking Smad signal transduction in vitro, but do not inhibit renal interstitial fibrosis in vivo.

Topics: Acetylcysteine; Actins; Animals; Cells, Cultured; Cysteine Proteinase Inhibitors; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibroblasts; Fibrosis; Kidney Diseases; Leupeptins; Male; Nerve Tissue Proteins; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Smad Proteins, Receptor-Regulated; Smad2 Protein; Smad3 Protein; Smad4 Protein; Transcription Factors; Transcription, Genetic; Transforming Growth Factor beta; Ureteral Obstruction