Abstract
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-α (TNF-α) to examine their response to bortezomib. To explore the mechanism behind it, we assessed the previously studied TNF-α/protein kinase B (Akt)/Smad ubiquitin regulatory factor 2 (Smurf2) signaling and performed RNA sequencing. Our results suggested that bortezomib could attenuate the TNF-α-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-κB) pathway by stabilizing inhibitor of NF-κB. The study highlighted the therapeutic potential of bortezomib on renal allograft interstitial fibrosis. Such an effect may result from inhibition of NF-κB/TNF-α/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of inhibitor of NF-κB.
Keywords:
Bortezomib; EMT; IκBα; chronic allograft dysfunction; kidney transplantation.
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Bortezomib / pharmacology*
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Cell Line
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Epithelial-Mesenchymal Transition / drug effects
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Fibrosis
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Graft Rejection / enzymology
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Graft Rejection / etiology
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Graft Rejection / pathology
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Graft Rejection / prevention & control*
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Graft Survival / drug effects
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Humans
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Kidney Diseases / enzymology
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Kidney Diseases / etiology
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Kidney Diseases / pathology
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Kidney Diseases / prevention & control*
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Kidney Transplantation / adverse effects*
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Kidney Tubules, Proximal / drug effects*
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Kidney Tubules, Proximal / enzymology
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Kidney Tubules, Proximal / pathology
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Male
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NF-KappaB Inhibitor alpha / metabolism
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NF-kappa B / metabolism
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Proteasome Inhibitors / pharmacology*
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Protein Stability
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Inbred F344
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Rats, Inbred Lew
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / metabolism
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism
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Ubiquitin-Protein Ligases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, rat
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Proteasome Inhibitors
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TNF protein, human
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Bortezomib
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SMURF2 protein, human
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Smurf2 protein, rat
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Ubiquitin-Protein Ligases
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MTOR protein, human
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mTOR protein, rat
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases