# Serum response factor targets Cyr61 to facilitate chronic progression after ischemic acute kidney injury through renal tubular epithelial–myofibroblast transdifferentiation

## TL;DR

This study shows that the SRF/Cyr61 pathway promotes kidney cell changes after injury, and blocking SRF may help prevent chronic kidney damage.

## Contribution

The study identifies SRF as a novel therapeutic target for chronic progression after ischemic acute kidney injury.

## Key findings

- SRF and Cyr61 are upregulated during EMyT in kidney cells after ischemic injury.
- Blocking SRF with CCG-1423 reduces EMyT and improves kidney function in models of AKI.
- SRF upregulation increases Cyr61 expression, which contributes to chronic kidney damage.

## Abstract

To explore the regulation and function of serum response factor (SRF)/cysteine-rich protein 61 (Cyr61) pathway in renal tubular epithelial–myofibroblast transdifferentiation (EMyT) in the chronic progression after ischemic acute kidney injury (AKI).

The expression of SRF, Cyr61, myofibroblast markers (collagen-3, α-SMA and vimentin) and epithelial markers (E-cadherin and ZO-1) were examined in mouse renal tubular epithelial cells (TCMK-1 cells) under hypoxia/reoxygenation (H/R) treatment or rat renal medulla tissue samples after ischemia/reperfusion (I/R) treatment. SRF was overexpressed by pcDNA–SRF plasmid and suppressed by CCG-1423 (a small molecule inhibitor of SRF) or SRF siRNA to study how SRF influences renal tubular EMyT through Cyr61 in the chronic progression after AKI.

In TCMK-1 cells under H/R treatment and renal medulla tissue from I/R rats, the SRF along with Cyr61, collagen-3, α-SMA and vimentin expression was upregulated, while E-cadherin and ZO-1 expression was downregulated. SRF upregulation in TCMK-1 cells increased Cyr61 expression. Blockade of SRF by an SRF-specific siRNA or CCG-1423 reduced Cyr61 induction, protected renal tubular epithelial cells from undergoing EMyT and improved the chronic progression after ischemic AKI both in vitro and in vivo.

Increased SRF/Cyr61 pathway activity promotes EMyT and dysfunction in renal tubular epithelial cells in the chronic progression after AKI. Targeting SRF with CCG-1423 may be an attractive therapeutic strategy in the chronic progression after AKI.