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Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition.


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, ?-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-?1/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-?1-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.

SUBMITTER: Tang PM 

PROVIDER: S-EPMC7456094 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition.

Tang Patrick Ming-Kuen PM   Zhang Ying-Ying YY   Xiao Jun J   Tang Philip Chiu-Tsun PC   Chung Jeff Yat-Fai JY   Li Jinhong J   Xue Vivian Weiwen VW   Huang Xiao-Ru XR   Chong Charing Ching-Ning CC   Ng Chi-Fai CF   Lee Tin-Lap TL   To Ka-Fai KF   Nikolic-Paterson David J DJ   Lan Hui-Yao HY  

Proceedings of the National Academy of Sciences of the United States of America 20200811 34


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 ma  ...[more]

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