Transcription Factor ATF3 Mediating SOCS3 Expression Aggravates Renal Ischemia-Reperfusion Injury by Activating Mitophagy.

Abstract

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, quantitative real-time polymerase chain reaction, 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, dual-luciferase reporter assay, and co-immunoprecipitation). 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 regulatory mechanism.

CONCLUSION:

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

• Authors: Yu Luo, Zhitao Cai, Xiongfei Wu, Feng Liu, Lian Li
• Journal: Nephron (Nephron) Vol. 148 Issue 4 Pg. 230-244 ( 2024) ISSN: 2235-3186 [Electronic] Switzerland
• PMID: 37956656 (Publication Type: Journal Article)
• Copyright: © 2023 S. Karger AG, Basel.

Chemical References

• Activating Transcription Factor 3

Topics

• Animals
• Mice
• Activating Transcription Factor 3 (genetics, metabolism, pharmacology)
• Gene Expression Regulation
• Kidney (pathology)
• Kidney Diseases (pathology)
• Mitophagy
• Reperfusion Injury (metabolism)