# ATF3 aggravates kidney fibrosis via HDAC6-dependent epigenetic reprogramming

## TL;DR

The study shows that ATF3 worsens kidney fibrosis by interacting with HDAC6, offering new insights into chronic kidney disease.

## Contribution

This study identifies ATF3 as a novel driver of kidney fibrosis through HDAC6-dependent epigenetic changes.

## Key findings

- ATF3 is significantly upregulated in damaged tubular epithelial cells during kidney fibrosis.
- ATF3 deletion in mice reduces fibrosis and prevents fibrotic traits in injured cells.
- ATF3 recruits HDAC6 to the SMAD7 promoter, suppressing SMAD7 and activating the TGF-β/Smad3 pathway.

## 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.