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Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition.
Tang, Patrick Ming-Kuen; Zhang, Ying-Ying; Xiao, Jun; Tang, Philip Chiu-Tsun; Chung, Jeff Yat-Fai; Li, Jinhong; Xue, Vivian Weiwen; Huang, Xiao-Ru; Chong, Charing Ching-Ning; Ng, Chi-Fai; Lee, Tin-Lap; To, Ka-Fai; Nikolic-Paterson, David J; Lan, Hui-Yao.
Afiliación
  • Tang PM; 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.
  • Zhang YY; 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.
  • Xiao J; 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.
  • Tang PC; Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
  • Chung JY; 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.
  • Li J; 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.
  • Xue VW; 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.
  • Huang XR; 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.
  • Chong CC; 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.
  • Ng CF; 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.
  • Lee TL; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, 510080, China.
  • To KF; SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, 999077, Hong Kong.
  • Nikolic-Paterson DJ; SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, 999077, Hong Kong.
  • Lan HY; Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, 999077, Hong Kong.
Proc Natl Acad Sci U S A ; 117(34): 20741-20752, 2020 08 25.
Article en En | MEDLINE | ID: mdl-32788346
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, α-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-ß1/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-ß1-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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteína smad3 / Factor de Transcripción Brn-3A / Factor de Crecimiento Transformador beta1 Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2020 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteína smad3 / Factor de Transcripción Brn-3A / Factor de Crecimiento Transformador beta1 Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2020 Tipo del documento: Article