PMID- 34252535
OWN - NLM
STAT- MEDLINE
DCOM- 20220331
LR  - 20220401
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 86
DP  - 2021 Oct
TI  - IL-6/STAT3 signaling activation exacerbates high fructose-induced podocyte 
      hypertrophy by ketohexokinase-A-mediated tristetraprolin down-regulation.
PG  - 110082
LID - S0898-6568(21)00171-6 [pii]
LID - 10.1016/j.cellsig.2021.110082 [doi]
AB  - Glomerular hypertrophy is a crucial factor of severe podocyte damage and 
      proteinuria. Our previous study showed that high fructose induced podocyte 
      injury. The current study aimed to explore a novel molecular mechanism underlying 
      podocyte hypertrophy induced by high fructose. Here we demonstrated for the first 
      time that high fructose significantly initiated the hypertrophy in rat glomeruli 
      and differentiated human podocytes (HPCs). Consistently, it induced inflammatory 
      response with the down-regulation of anti-inflammatory factor zinc-finger protein 
      tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal 
      transducer and activator of transcription 3 (STAT3) signaling in these animal and 
      cell models. Subsequently, high-expression of microRNA-92a-3p (miR-92a-3p) and 
      its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, 
      representing abnormal proliferation and apoptosis, were observed in vivo and in 
      vitro. Moreover, high fructose increased ketohexokinase-A (KHK-A) expression in 
      rat glomeruli and differentiated HPCs. Exogenous IL-6 stimulation up-regulated 
      IL-6/STAT3 signaling and miR-92a-3p, reduced P57 expression and promoted podocyte 
      proliferation, apoptosis and hypertrophy in vitro. The data from 
      anti-inflammatory agent maslinic acid treatment or TTP siRNA transfection showed 
      that high fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte 
      overproliferation and apoptosis, causing podocyte hypertrophy. Whereas, KHK-A 
      siRNA transfection remarkably restored high fructose-induced TTP down-regulation, 
      IL-6/STAT3 signaling activation, podocyte overproliferation, apoptosis and 
      hypertrophy in differentiated HPCs. Taken together, these results suggested that 
      high fructose possibly increased KHK-A expression to down-regulate TTP, 
      subsequently activated IL-6/STAT3 signaling to interfere with podocyte 
      proliferation and apoptosis by up-regulating miR-92a-3p to suppress P57 
      expression, causing podocyte hypertrophy. Therefore, the inactivation of 
      IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to 
      increase TTP may be a novel strategy for high fructose diet-associated podocyte 
      injury and proteinuria.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Zhou, Jie
AU  - Zhou J
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Yang, Jie
AU  - Yang J
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Wang, Yu-Meng
AU  - Wang YM
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Ding, Hong
AU  - Ding H
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Li, Tu-Shuai
AU  - Li TS
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Liu, Zhi-Hong
AU  - Liu ZH
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Chen, Li
AU  - Chen L
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Jiao, Rui-Qing
AU  - Jiao RQ
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Zhang, Dong-Mei
AU  - Zhang DM
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China.
FAU - Kong, Ling-Dong
AU  - Kong LD
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing 210023, PR China. Electronic address: 
      kongld@nju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210710
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Interleukin-6)
RN  - 0 (MicroRNAs)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Tristetraprolin)
RN  - 30237-26-4 (Fructose)
RN  - EC 2.7.1.- (Fructokinases)
SB  - IM
MH  - Animals
MH  - Down-Regulation
MH  - Fructokinases/genetics/metabolism
MH  - Fructose/metabolism
MH  - Hypertrophy/metabolism
MH  - Interleukin-6/metabolism
MH  - *MicroRNAs/genetics/metabolism
MH  - *Podocytes/metabolism
MH  - Rats
MH  - STAT3 Transcription Factor/metabolism
MH  - Tristetraprolin/genetics/metabolism
OTO - NOTNLM
OT  - High fructose diet
OT  - IL-6
OT  - KHK-A
OT  - Podocyte hypertrophy
OT  - Podocyte overproliferation
OT  - TTP
EDAT- 2021/07/13 06:00
MHDA- 2022/04/01 06:00
CRDT- 2021/07/12 20:17
PHST- 2021/03/29 00:00 [received]
PHST- 2021/06/25 00:00 [revised]
PHST- 2021/07/06 00:00 [accepted]
PHST- 2021/07/13 06:00 [pubmed]
PHST- 2022/04/01 06:00 [medline]
PHST- 2021/07/12 20:17 [entrez]
AID - S0898-6568(21)00171-6 [pii]
AID - 10.1016/j.cellsig.2021.110082 [doi]
PST - ppublish
SO  - Cell Signal. 2021 Oct;86:110082. doi: 10.1016/j.cellsig.2021.110082. Epub 2021 
      Jul 10.