AUF1 modulates TGF-β signal in renal tubular epithelial cells via post-transcriptional regulation of Nedd4L expression.

Posttranscriptional regulation process plays important roles in renal disease pathogenesis. AU-rich element RNA-binding protein (AUF1) interacts with and destabilizes mRNAs containing AU-rich elements (AREs) in their 3'UTR. The current study demonstrated that AUF1 was increased in unilateral ureteral obstruction (UUO) animal models. While proliferation and migration of HK2 cells was unaltered by AUF1 downregulation under normal condition, proliferative inhibition and migratory promotion mediated by TGF-β was significantly compromised. Mechanically, AUF1 downregulation decreased phosphorylated Smad2/3 via increasing their E3 ligase Nedd4L at the posttranscriptional level. In addition, the current study identified Nedd4L as a previously unreported target of AUF1. AUF1 regulates Nedd4L expression at the posttranscriptional level by interaction with AREs in the 3'UTR of the Nedd4L mRNA. Collectively, the current study indicates that AUF1 might be a potential player in renal tubulointerstitial fibrosis through modulation of TGF-β signal transduction via posttranscriptional regulation of Nedd4L.

Yan J ，Du F ，Li SD ，Yuan Y ，Jiang JY ，Li S ，Li XY ，Du ZX ... -  《BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH》

Diminution of microRNA-98 alleviates renal fibrosis in diabetic nephropathy by elevating Nedd4L and inactivating TGF-β/Smad2/3 pathway.

Zeng Y ，Feng Z ，Liao Y ，Yang M ，Bai Y ，He Z ... -  《-》

Interaction between 3' untranslated region of calcitonin receptor messenger ribonucleic acid (RNA) and adenylate/uridylate (AU)-rich element binding proteins (AU-rich RNA-binding factor 1 and Hu antigen R).

Yasuda S ，Wada S ，Arao Y ，Kogawa M ，Kayama F ，Katayama S ... -  《ENDOCRINOLOGY》

Effects of proteasome inhibitors on rat renal fibrosis in vitro and in vivo.

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.

Sakairi T ，Hiromura K ，Takahashi S ，Hamatani H ，Takeuchi S ，Tomioka M ，Maeshima A ，Kuroiwa T ，Nojima Y ... -  《-》

Association of the von Hippel-Lindau protein with AUF1 and posttranscriptional regulation of VEGFA mRNA.

Xin H ，Brown JA ，Gong C ，Fan H ，Brewer G ，Gnarra JR ... -  《-》