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ATF3 aggravates kidney fibrosis via HDAC6-dependent epigenetic reprogramming
Sibei Tao1, Chenzhou Wu2, Fanyuan Yu2
1Division of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Abstract:
Kidney fibrosis is the most common pathology and endpoint of CKD. Unraveling the mechanisms of kidney fibrosis is crucial. Activating transcription factors (ATFs) are implicated in a range of kidney diseases, but their roles in kidney fibrosis remain underexplored. In our investigation, employing an unbiased screening of ATF expression in fibrotic kidneys via analyzing single-cell and bulk RNA sequencing, we identified that ATF3 as the key player, markedly upregulated in damaged tubular epithelial cells (TECs). Crucially, ATF3 deletion in mice markedly attenuated kidney fibrosis and abrogated fibrotic traits in injured TECs. At the molecular level, ATF3 was found to recruit HDAC6 to the SMAD7 promoter, eradicating histone 3 lysine 14 acetylation (H3K14ac) and diminishing SMAD7 transcription. This interaction between ATF3 and HDAC6 culminated in the suppression of Smad7, triggering the TGF-β/Smad3 pathway and exacerbating kidney fibrosis. Collectively, our findings shed light on the complex underpinnings of kidney fibrosis and herald novel therapeutic targets for combating CKD.
Insights
Activating transcription factor 3 (ATF3) drives kidney fibrosis by suppressing SMAD7. ATF3 deletion in mice significantly reduced kidney fibrosis, revealing a new therapeutic target for chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Biology
Background:
- Kidney fibrosis is a common outcome of chronic kidney disease (CKD), necessitating a deeper understanding of its underlying mechanisms.
- Activating transcription factors (ATFs) are involved in kidney diseases, but their specific roles in kidney fibrosis are not well understood.
Purpose of the Study:
- To investigate the role of Activating Transcription Factors (ATFs) in kidney fibrosis.
- To identify key molecular players driving kidney fibrosis and explore potential therapeutic targets for CKD.
Main Methods:
- Unbiased screening of ATF expression in fibrotic kidneys using single-cell and bulk RNA sequencing.
- Analysis of ATF3's molecular function in kidney fibrosis using mouse models with ATF3 deletion.
- Investigation of ATF3's interaction with HDAC6 and its effect on SMAD7 promoter activity and transcription.
Main Results:
- ATF3 was identified as a key ATF, significantly upregulated in damaged tubular epithelial cells (TECs) in fibrotic kidneys.
- Deletion of ATF3 in mice markedly attenuated kidney fibrosis and reversed fibrotic traits in injured TECs.
- ATF3 recruits HDAC6 to the SMAD7 promoter, leading to reduced H3K14ac, diminished SMAD7 transcription, and subsequent activation of the TGF-β/Smad3 pathway, exacerbating fibrosis.
Conclusions:
- ATF3 plays a critical role in promoting kidney fibrosis by suppressing SMAD7 expression via the ATF3-HDAC6-SMAD7 axis.
- Targeting the ATF3 pathway presents a promising novel therapeutic strategy for combating kidney fibrosis and CKD.
