Transcription factor ATF3 mediating SOCS3 expression aggravates renal ischemia-reperfusion injury by activating mitophagy.

INTRODUCTION: Suppressor of cytokine signaling 3 (SOCS3) is highly expressed in mice with renal ischemia/reperfusion (RI/R) injury and has the potential to regulate mitophagy. On this basis, this study further investigates the possible mechanism via which SOCS3 affects RI/R by regulating mitophagy.

METHOD: After establishing a RI/R injury mouse model and a hypoxia/reoxygenation (H/R) cell model, the effects of silenced SOCS3 on injury and mitophagy in the above models were analyzed by ELISA, qRT-PCR, Western blot, pathological sections, CCK-8 assay, flow cytometry and JC-1 assay. Mechanistic studies were carried out with the help of database analysis and binding validation experiments (chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay and Co-Immunoprecipitation (Co-IP)). After the binding target was identified, the regulatory relationship between the target gene and SOCS3 was verified by rescue experiments.

RESULT: The large increase in blood urea nitrogen (BUN) and creatinine (Cr) levels verified the success of the RI/R model. SOCS3 expression was up-regulated in RI/R mice. Silenced SOCS3 alleviated kidney damage and mitochondrial abnormalities in RI/R mice, and inhibited mitophagy at the molecular level. Likewise, silenced SOCS3 alleviated H/R-induced cell damage and mitophagy. Finally, activating transcription factor 3 (ATF3) was determined to bind to the promoter of SOCS3, which interacted with insulin-like growth factor 1 receptor (IGF1R). Rescue experiments confirmed the effect of ATF3 on SOCS3 expression and the underlying regulation mechanism.

CONCLUSION: ATF3 mediates SOCS3 expression to promote the activation of mitophagy, thereby aggravating renal ischemia-reperfusion injury.