PMID- 32788346
OWN - NLM
STAT- MEDLINE
DCOM- 20201028
LR  - 20220317
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 34
DP  - 2020 Aug 25
TI  - Neural transcription factor Pou4f1 promotes renal fibrosis via 
      macrophage-myofibroblast transition.
PG  - 20741-20752
LID - 10.1073/pnas.1917663117 [doi]
AB  - Unresolved inflammation can lead to tissue fibrosis and impaired organ function. 
      Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by 
      which ongoing chronic inflammation causes progressive fibrosis in different forms 
      of kidney disease. However, the mechanisms underlying MMT are still largely 
      unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 
      (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is 
      highly expressed by macrophages undergoing MMT in sites of fibrosis in human and 
      experimental kidney disease, identified by coexpression of the myofibroblast 
      marker, alpha-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal 
      fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in 
      vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified 
      that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while 
      microarray analysis defined a Pou4f1-dependent fibrogenic gene network for 
      promoting TGF-beta1/Smad3-driven MMT in BMDMs at the transcriptional level. More 
      importantly, using two mouse models of progressive renal interstitial fibrosis 
      featuring the MMT process, we demonstrated that adoptive transfer of 
      TGF-beta1-stimulated BMDMs restored both MMT and renal fibrosis in 
      macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred 
      BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and 
      suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with 
      progressive renal fibrosis.
FAU - Tang, Patrick Ming-Kuen
AU  - Tang PM
AUID- ORCID: 0000-0002-3194-3736
AD  - Department of Anatomical and Cellular Pathology, State Key Laboratory of 
      Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong 
      Kong, 999077, Hong Kong; patrick.tang@cuhk.edu.hk hylan@cuhk.edu.hk.
AD  - Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, 
      Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Zhang, Ying-Ying
AU  - Zhang YY
AD  - Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, 
      Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
AD  - Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, 
      Shanghai, 200065, China.
FAU - Xiao, Jun
AU  - Xiao J
AUID- ORCID: 0000-0003-4004-3382
AD  - Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, 
      Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Tang, Philip Chiu-Tsun
AU  - Tang PC
AD  - Department of Anatomical and Cellular Pathology, State Key Laboratory of 
      Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Chung, Jeff Yat-Fai
AU  - Chung JY
AD  - Department of Anatomical and Cellular Pathology, State Key Laboratory of 
      Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Li, Jinhong
AU  - Li J
AD  - Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, 
      Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Xue, Vivian Weiwen
AU  - Xue VW
AD  - Department of Anatomical and Cellular Pathology, State Key Laboratory of 
      Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Huang, Xiao-Ru
AU  - Huang XR
AD  - Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, 
      Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
AD  - Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney 
      Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People's 
      Hospital, Guangzhou, 510080, China.
FAU - Chong, Charing Ching-Ning
AU  - Chong CC
AUID- ORCID: 0000-0002-8425-8767
AD  - SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, 
      999077, Hong Kong.
FAU - Ng, Chi-Fai
AU  - Ng CF
AUID- ORCID: 0000-0002-1723-9646
AD  - SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, 
      999077, Hong Kong.
FAU - Lee, Tin-Lap
AU  - Lee TL
AD  - Reproduction, Development and Endocrinology Program, School of Biomedical 
      Sciences, The Chinese University of Hong Kong, 999077, Hong Kong.
FAU - To, Ka-Fai
AU  - To KF
AD  - Department of Anatomical and Cellular Pathology, State Key Laboratory of 
      Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong 
      Kong, 999077, Hong Kong.
FAU - Nikolic-Paterson, David J
AU  - Nikolic-Paterson DJ
AUID- ORCID: 0000-0001-5734-2931
AD  - Department of Nephrology and Monash University Department of Medicine, Monash 
      Medical Centre, Clayton, VIC 3168, Australia.
FAU - Lan, Hui-Yao
AU  - Lan HY
AD  - Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, 
      Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong 
      Kong, 999077, Hong Kong; patrick.tang@cuhk.edu.hk hylan@cuhk.edu.hk.
AD  - Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney 
      Diseases, The Chinese University of Hong Kong, 999077, Hong Kong.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200811
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (POU4F1 protein, human)
RN  - 0 (Pou4f1 protein, mouse)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad3 Protein)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transcription Factor Brn-3A)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta1)
SB  - IM
CIN - J Urol. 2021 May;205(5):1517-1519. PMID: 33625915
EIN - Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2200781119. PMID: 35245173
MH  - Animals
MH  - Female
MH  - Fibrosis/physiopathology
MH  - Gene Regulatory Networks
MH  - Humans
MH  - Inflammation/pathology
MH  - Kidney/pathology
MH  - Kidney Diseases/genetics
MH  - Macrophages/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myofibroblasts/metabolism
MH  - Signal Transduction/genetics
MH  - Smad3 Protein/*metabolism
MH  - Transcription Factor Brn-3A/*genetics/metabolism/physiology
MH  - Transforming Growth Factor beta/metabolism
MH  - Transforming Growth Factor beta1/*metabolism
MH  - Urinary Tract/metabolism
PMC - PMC7456094
OTO - NOTNLM
OT  - Pou4f1
OT  - macrophage-myofibroblast transition
OT  - renal fibrosis
COIS- The authors declare no competing interest.
EDAT- 2020/08/14 06:00
MHDA- 2020/10/29 06:00
PMCR- 2021/02/11
CRDT- 2020/08/14 06:00
PHST- 2020/08/14 06:00 [pubmed]
PHST- 2020/10/29 06:00 [medline]
PHST- 2020/08/14 06:00 [entrez]
PHST- 2021/02/11 00:00 [pmc-release]
AID - 1917663117 [pii]
AID - 201917663 [pii]
AID - 10.1073/pnas.1917663117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20741-20752. doi: 
      10.1073/pnas.1917663117. Epub 2020 Aug 11.