DRD4 alleviates acute kidney injury by suppressing ISG15/NOX4 axis-associated oxidative stress

Area of Science:

• Nephrology
• Molecular Biology
• Pharmacology

Background:

• Acute kidney injury (AKI) presents significant morbidity and mortality, with limited clinical prediction and treatment options.
• Oxidative stress and mitochondrial dysfunction are key contributors to AKI pathogenesis.
• The dopamine D4 receptor (DRD4) is implicated in oxidative stress pathways.

Purpose of the Study:

• To investigate the protective role of DRD4 against acute kidney injury.
• To elucidate the mechanisms by which DRD4 may attenuate nephrotoxicity.

Main Methods:

• In vivo studies using mouse models of ischemia/reperfusion injury (IRI) and cisplatin-induced nephrotoxicity.
• In vitro experiments with HK-2 cells subjected to hypoxia/reoxygenation or cisplatin.
• Transcriptome sequencing to identify downstream targets and molecular pathways.

Main Results:

• DRD4 expression was significantly reduced in kidneys following IRI or cisplatin treatment.
• DRD4 administration attenuated nephrotoxicity by suppressing reactive oxygen species (ROS) and NADPH oxidase 4 (NOX4) expression, enhancing mitochondrial function.
• DRD4 protected HK-2 cells from oxidative stress-induced apoptosis.
• Mechanistically, DRD4 downregulated ISG15, leading to reduced NOX4 ISGylation, increased NOX4 ubiquitination, and subsequent degradation.

Conclusions:

• DRD4 exhibits significant protective effects against both IRI and cisplatin-induced AKI.
• DRD4 acts by mitigating oxidative stress and apoptosis, partly through the ISG15-NOX4 pathway.
• DRD4 represents a promising therapeutic target for preventing and treating acute kidney injury.