Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage–myofibroblast transition

Patrick Ming Kuen Tang, Ying Ying Zhang, Jun Xiao, Philip Chiu Tsun Tang, Jeff Yat Fai Chung, Jinhong Li, Vivian Weiwen Xue, Xiao Ru Huang, Charing Ching Ning Chong, Chi Fai Ng, Tin Lap Lee, Ka Fai To, David J. Nikolic-Paterson, Hui Yao Lan

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22 Citations (Scopus)

Abstract

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 TGFβ1/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-β1-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.

Original languageEnglish
Pages (from-to)20741-20752
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number34
DOIs
Publication statusPublished - 25 Aug 2020

Keywords

  • Macrophage–myofibroblast transition
  • Pou4f1
  • Renal fibrosis

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