Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition.
Patrick Ming-Kuen TangYing-Ying ZhangJun XiaoPhilip Chiu-Tsun TangJeff Yat-Fai ChungJinhong LiVivian Weiwen XueXiao-Ru HuangCharing Ching Ning ChongChi-Fai NgTin-Lap LeeKa-Fai ToDavid J Nikolic PatersonHui-Yao LanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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-β1/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.
Keyphrases
- transforming growth factor
- transcription factor
- early stage
- chronic kidney disease
- multiple sclerosis
- adipose tissue
- epithelial mesenchymal transition
- oxidative stress
- liver fibrosis
- gene expression
- type diabetes
- poor prognosis
- squamous cell carcinoma
- endothelial cells
- binding protein
- genome wide
- dna damage
- metabolic syndrome
- dna binding
- rectal cancer
- high fat diet induced
- amino acid
- genome wide identification
- neoadjuvant chemotherapy
- induced pluripotent stem cells