PMID- 31637729
OWN - NLM
STAT- MEDLINE
DCOM- 20210308
LR  - 20210308
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 235
IP  - 5
DP  - 2020 May
TI  - MKL1 mediates TGF-beta-induced CTGF transcription to promote renal fibrosis.
PG  - 4790-4803
LID - 10.1002/jcp.29356 [doi]
AB  - Aberrant fibrogenesis impairs the architectural and functional homeostasis of the 
      kidneys. It also predicts poor diagnosis in patients with end-stage renal disease 
      (ESRD). Renal tubular epithelial cells (RTEC) can trans-differentiate into 
      myofibroblasts to produce extracellular matrix proteins and contribute to renal 
      fibrosis. Connective tissue growth factor (CTGF) is a cytokine upregulated in 
      RTECs during renal fibrosis. In the present study, we investigated the regulation 
      of CTGF transcription by megakaryocytic leukemia 1 (MKL1). Genetic deletion or 
      pharmaceutical inhibition of MKL1 in mice mitigated renal fibrosis following the 
      unilateral ureteral obstruction procedure. Notably, MKL1 deficiency in mice 
      downregulated CTGF expression in the kidneys. Likewise, MKL1 knockdown or 
      inhibition in RTEs blunted TGF-beta induced CTGF expression. Further, it was 
      discovered that MKL1 bound directly to the CTGF promoter by interacting with 
      SMAD3 to activate CTGF transcription. In addition, MKL1 mediated the interplay 
      between p300 and WDR5 to regulate CTGF transcription. CTGF knockdown dampened 
      TGF-beta induced pro-fibrogenic response in RTEs. MKL1 activity was reciprocally 
      regulated by CTGF. In conclusion, we propose that targeting the MKL1-CTGF axis 
      may generate novel therapeutic solutions against aberrant renal fibrogenesis.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - Mao, Lei
AU  - Mao L
AD  - Department of Pathophysiology, Key Laboratory of Targeted Intervention of 
      Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular 
      Translational Medicine, Nanjing Medical University, Nanjing, China.
FAU - Liu, Li
AU  - Liu L
AD  - Department of Pathophysiology, Key Laboratory of Targeted Intervention of 
      Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular 
      Translational Medicine, Nanjing Medical University, Nanjing, China.
FAU - Zhang, Tianyi
AU  - Zhang T
AD  - Department of Pathophysiology, Key Laboratory of Targeted Intervention of 
      Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular 
      Translational Medicine, Nanjing Medical University, Nanjing, China.
FAU - Wu, Xiaoyan
AU  - Wu X
AD  - Department of Pathophysiology, Key Laboratory of Targeted Intervention of 
      Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular 
      Translational Medicine, Nanjing Medical University, Nanjing, China.
AD  - The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, 
      Nanjing, China.
FAU - Zhang, Tao
AU  - Zhang T
AD  - Department of Geriatric Nephrology, Jiangsu Province Hospital, First Affiliated 
      Hospital of Nanjing Medical University, Nanjing, China.
FAU - Xu, Yong
AU  - Xu Y
AUID- ORCID: 0000-0003-1470-9371
AD  - Department of Pathophysiology, Key Laboratory of Targeted Intervention of 
      Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular 
      Translational Medicine, Nanjing Medical University, Nanjing, China.
AD  - Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191021
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (CCN2 protein, mouse)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Mrtfa protein, mouse)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad3 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Wdr5 protein, mouse)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
RN  - EC 2.3.1.48 (E1A-Associated p300 Protein)
RN  - EC 2.3.1.48 (Ep300 protein, mouse)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - Connective Tissue Growth Factor/genetics/*metabolism
MH  - Disease Models, Animal
MH  - E1A-Associated p300 Protein/metabolism
MH  - Epigenesis, Genetic
MH  - Fibrosis
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Kidney/*drug effects/enzymology/pathology
MH  - Kidney Diseases/*enzymology/etiology/genetics/pathology
MH  - Male
MH  - Mice, Knockout
MH  - Promoter Regions, Genetic
MH  - Rats
MH  - Signal Transduction
MH  - Smad3 Protein/metabolism
MH  - Trans-Activators/deficiency/genetics/*metabolism
MH  - Transcription, Genetic/*drug effects
MH  - Transforming Growth Factor beta/*pharmacology
MH  - Ureteral Obstruction/complications
OTO - NOTNLM
OT  - epigenetics
OT  - renal fibrosis
OT  - transcription factor
OT  - transcriptional regulation
EDAT- 2019/10/23 06:00
MHDA- 2021/03/09 06:00
CRDT- 2019/10/23 06:00
PHST- 2019/04/04 00:00 [received]
PHST- 2019/09/30 00:00 [accepted]
PHST- 2019/10/23 06:00 [pubmed]
PHST- 2021/03/09 06:00 [medline]
PHST- 2019/10/23 06:00 [entrez]
AID - 10.1002/jcp.29356 [doi]
PST - ppublish
SO  - J Cell Physiol. 2020 May;235(5):4790-4803. doi: 10.1002/jcp.29356. Epub 2019 Oct 
      21.