Journal
CLINICAL SCIENCE
Volume 135, Issue 1, Pages 53-69Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20201038
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Funding
- National Natural Science Foundation of China [81770751, 81470981]
- 333 High Level Talents Project in Jiangsu Province [BRA2017532, BRA2016514]
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The study showed that bortezomib attenuated TNF-α-induced epithelial-mesenchymal transition and renal allograft interstitial fibrosis by inhibiting NF-κB/TNF-α/Akt/mTOR/p70S6 kinase/Smurf2 signaling and stabilizing the inhibitor of NF-κB protein.
Chronic allograft dysfunction is a major cause of late graft failure after kidney transplantation. One of the histological changes is interstitial fibrosis, which is associated with epithelial-mesenchymal transition. Bortezomib has been reported to prevent the progression of fibrosis in organs. We used rat renal transplantation model and human kidney 2 cell line treated with tumor necrosis factor-alpha (TNF-alpha) to examine their response to bortezomib. To explore the mechanism behind it, we assessed the previously studied TNF-alpha/protein kinase B (Akt)/Smad ubiquitin regulatory factor 2 (Smurf2) signaling and performed RNA sequencing. Our results suggested that bortezomib could attenuate the TNF-alpha-induced epithelial-mesenchymal transition and renal allograft interstitial fibrosis in vitro and in vivo. In addition to blocking Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase/Smurf2 signaling, bortezomib's effect on the epithelial-mesenchymal transition was associated with inhibition of nuclear factor kappa B (NF-kappa B) pathway by stabilizing inhibitor of NF-kappa B. The study highlighted the therapeutic potential of bortezomib on renal allograft interstitial fibrosis. Such an effect may result from inhibition of NF-kappa B/TNF-alpha/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of inhibitor of NF-kappa B.
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