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Title: | Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition. | Authors: | Lan H.-Y.;Nikolic-Paterson D.J. ;Tang P.M.-K.;Zhang Y.-Y.;Xiao J.;Tang P.C.-T.;Chung J.Y.-F.;Li J.;Xue V.W.;Huang X.-R.;Chong C.C.-N.;Ng C.-F.;Lee T.-L.;To K.-F. | Institution: | (Tang, Tang, Chung, Xue, To) Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong 999077, Hong Kong (Tang, Zhang, Xiao, Li, Huang, Lan) Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, Chinese University of Hong Kong, Hong Kong 999077, Hong Kong (Zhang) Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China (Huang) Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou 510080, China (Chong, Ng) SH Ho Urology Centre, Department of Surgery, Chinese University of Hong Kong, Hong Kong 999077, Hong Kong (Lee) Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong 999077, Hong Kong (Nikolic-Paterson) Department of Nephrology, Monash University, Clayton, VIC 3168, Australia (Nikolic-Paterson) Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia (Lan) Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Chinese University of Hong Kong, Hong Kong 999077, Hong Kong | Issue Date: | 20-Nov-2020 | Copyright year: | 2020 | Publisher: | National Academy of Sciences | Place of publication: | United States | Publication information: | Proceedings of the National Academy of Sciences of the United States of America. 117 (34) (pp 20741-20752), 2020. Date of Publication: 25 Aug 2020. | Journal: | Proceedings of the National Academy of Sciences of the United States of America | 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, 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 TGFbeta1/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.Copyright © 2020 National Academy of Sciences. All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1073/pnas.1917663117 | PubMed URL: | 32788346 [http://www.ncbi.nlm.nih.gov/pubmed/?term=32788346] | ISSN: | 0027-8424 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/28969 | Type: | Article | Subjects: | *myofibroblast nonhuman pathogenesis priority journal promoter region renal ischemia reperfusion injury/et [Etiology] upregulation ureter obstruction/et [Etiology] alpha smooth muscle actin/ec [Endogenous Compound] Smad3 protein/ec [Endogenous Compound] *transcription factor POU4F1 transforming growth factor beta1/ec [Endogenous Compound] a SMA gene *POU4F1 gene SMAD3 gene in vivo study animal cell animal experiment animal model animal tissue article bone marrow derived macrophage cell infiltration *cell interaction chromatin immunoprecipitation clinical article controlled study fibrogenesis gene expression gene silencing gene targeting genetic transcription human human cell human tissue in vitro study *kidney fibrosis/et [Etiology] kidney tissue *macrophage male microarray analysis mouse fibrogenesis gene expression gene silencing gene targeting genetic transcription human human cell human tissue in vitro study in vivo study *kidney fibrosis / *etiology kidney tissue *macrophage male microarray analysis mouse *myofibroblast nonhuman pathogenesis priority journal promoter region renal ischemia reperfusion injury / etiology animal model ureter obstruction / etiology animal experiment animal cell upregulation animal tissue Article bone marrow derived macrophage cell infiltration *cell interaction chromatin immunoprecipitation clinical article controlled study |
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