Targeted Restoration of GPX3 Attenuates Renal Ischemia/Reperfusion Injury by Balancing Selenoprotein Expression and Inhibiting ROS-mediated Mitochondrial Apoptosis

Background: Renal ischemia/reperfusion (IR) injury is the leading cause of acute kidney injury in both autologous and transplanted kidneys. Low-level Glutathione Peroxidase 3 (GPX3) is associated with renal IR injury. The exact mechanism of targeted GPX3 restoration in renal IR injury has yet to be determined.

Methods: The distribution of GPX3 in different tissues and organs of the body was investigated. The level of GPX3 in renal IR injury was assessed. To confirm the action of GPX3 and its mechanisms, IR models were used to introduce adeno-associated virus 9 containing GPX3, as well as hypoxia/reoxygenation-exposed normal rat kidney cells that consistently overexpressed GPX3. Reverse molecular docking was used to confirm whether GPX3 was a target of ebselen.

Results: GPX3 is abundant in the kidneys and decreases in expression during renal IR injury. GPX3 overexpression reduced renal IR injury and protected tubular epithelial cells from Apoptosis. Proteomics analysis revealed a strong link between GPX3 and mitochondrial signaling, cellular redox state, and different expression patterns of selenoproteins. GPX3 inhibited reactive oxygen species-induced mitochondrial Apoptosis and balanced the disordered expression of selenoproteins. GPX3 was identified as a stable selenoprotein that interacts with ebselen. Ebselen enhanced the level of GPX3 and reduced IR-induced mitochondrial damage and renal dysfunction.

Conclusions: Targeted restoration of GPX3 attenuates renal IR injury by balancing selenoprotein expression and inhibiting reactive oxygen species-mediated mitochondrial Apoptosis, indicating that GPX3 could be a potential therapeutic target for renal IR injury.