Serum Response Factor Regulates CCN1 to Exacerbate Acute Kidney Injury Through Facilitation of Ferroptosis-Related Injury.

AIM: To explore the regulation and function of serum response factor (SRF)/Cellular communication network factor 1 (CCN1) pathway in ferroptosis in ischemia/reperfusion (I/R) acute kidney injury (AKI).

METHODS

The level of SRF, CCN1, ferroptosis markers (TFR1, ACSL4, xCT, GPX4), ROS and SOD were examined in HK-2 cells under hypoxia/reoxygenation (H/R) treatment or rat renal tissue samples after 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 ferroptosis through CCN1 in I/R AKI.

RESULTS

In HK-2 cells under H/R treatment and renal tissue from I/R rats, the SRF along with CCN1, TFR1 and ACSL4 expression was upregulated, while xCT and GPX4 expression was downregulated. SRF upregulation in HK-2 cells increased CCN1 expression and was associated with ferroptosis-related changes. Blockade of SRF by CCG-1423 or an SRF-specific siRNA reduced CCN1 induction, protected renal tubular epithelial cells from ferroptosis-related injury, and alleviated I/R AKI both in vitro and in vivo.

CONCLUSION

Increased SRF/CCN1 pathway activity may be associated with ferroptosis-related injury and dysfunction in renal tubular epithelial cells during AKI. Targeting SRF with CCG-1423 may represent a potential therapeutic strategy of AKI.