PMID- 33289516
OWN - NLM
STAT- MEDLINE
DCOM- 20210816
LR  - 20240226
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 135
IP  - 1
DP  - 2021 Jan 15
TI  - Bortezomib limits renal allograft interstitial fibrosis by inhibiting 
      NF-kappaB/TNF-alpha/Akt/mTOR/P70S6K/Smurf2 pathway via IkappaBalpha protein stabilization.
PG  - 53-69
LID - 10.1042/CS20201038 [doi]
AB  - 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-kappaB) pathway by stabilizing inhibitor of NF-kappaB. The study 
      highlighted the therapeutic potential of bortezomib on renal allograft 
      interstitial fibrosis. Such an effect may result from inhibition of 
      NF-kappaB/TNF-alpha/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of 
      inhibitor of NF-kappaB.
CI  - (c) 2021 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Suo, Chuanjian
AU  - Suo C
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Gui, Zeping
AU  - Gui Z
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Wang, Zijie
AU  - Wang Z
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Zhou, Jiajun
AU  - Zhou J
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Zheng, Ming
AU  - Zheng M
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Chen, Hao
AU  - Chen H
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Fei, Shuang
AU  - Fei S
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Gu, Min
AU  - Gu M
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
FAU - Tan, Ruoyun
AU  - Tan R
AD  - Department of Urology, the First Affiliated Hospital of Nanjing Medical 
      University, Jiangsu Province Hospital, Nanjing 210029, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Nfkbia protein, rat)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (TNF protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 69G8BD63PP (Bortezomib)
RN  - EC 2.3.2.26 (SMURF2 protein, human)
RN  - EC 2.3.2.26 (Smurf2 protein, rat)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Bortezomib/*pharmacology
MH  - Cell Line
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Fibrosis
MH  - Graft Rejection/enzymology/etiology/pathology/*prevention & control
MH  - Graft Survival/drug effects
MH  - Humans
MH  - Kidney Diseases/enzymology/etiology/pathology/*prevention & control
MH  - Kidney Transplantation/*adverse effects
MH  - Kidney Tubules, Proximal/*drug effects/enzymology/pathology
MH  - Male
MH  - NF-KappaB Inhibitor alpha/metabolism
MH  - NF-kappa B/metabolism
MH  - Proteasome Inhibitors/*pharmacology
MH  - Protein Stability
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats, Inbred F344
MH  - Rats, Inbred Lew
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Time Factors
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - Rats
OTO - NOTNLM
OT  - Bortezomib
OT  - EMT
OT  - IkappaBalpha
OT  - chronic allograft dysfunction
OT  - kidney transplantation
EDAT- 2020/12/09 06:00
MHDA- 2021/08/17 06:00
CRDT- 2020/12/08 08:34
PHST- 2020/08/12 00:00 [received]
PHST- 2020/11/26 00:00 [revised]
PHST- 2020/12/08 00:00 [accepted]
PHST- 2020/12/09 06:00 [pubmed]
PHST- 2021/08/17 06:00 [medline]
PHST- 2020/12/08 08:34 [entrez]
AID - 227193 [pii]
AID - 10.1042/CS20201038 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2021 Jan 15;135(1):53-69. doi: 10.1042/CS20201038.