ATF3 aggravates kidney fibrosis via HDAC6-dependent epigenetic reprogramming

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.