image: (A) The experimental process in animals. (B) Immunohistochemistry-stained GPX3 expression levels in rat kidney tissues from each group. (C) Western blot bands of GPX3 expression levels in rat kidney tissues from each group. (D) A statistical plot of the expression levels of urea nitrogen and creatinine in the serum of rats in each group. (E) Hematoxylin-eosin-stained and immunohistochemistry-stained NGAL expression levels in the kidney tissues of rats in each group. (F) Western blot bands of NGAL and BAX expression levels in rat kidney tissues from each group. (G) Western blot band statistics.
Credit: Jun Pei, Jie Zhang, Chengjun Yu, Jin Luo, Sheng Wen, Yi Hua, Guanghui Wei
This new study published in Genes & Diseases by researchers from Children's Hospital of Chongqing Medical University and Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering identifies selenoprotein glutathione peroxidase 3 (GPX3) as a critical endogenous protector against renal IRI. Using both in vivo rat models and in vitro hypoxia–reoxygenation systems, the researchers demonstrate that GPX3 plays a central role in limiting inflammation, oxidative damage, and renal dysfunction following ischemic insult.
The researchers show that renal IRI leads to a pronounced reduction in GPX3 expression, coinciding with impaired renal function, tubular structural damage, increased apoptosis, and heightened inflammatory cytokine production. Restoring GPX3 expression through viral overexpression markedly improved renal functional indices, reduced histopathological injury, and alleviated tubular epithelial cell death. These findings establish GPX3 as an essential determinant of renal resilience during ischemia–reperfusion stress.
Mechanistic analyses revealed that GPX3 exerts its protective effects by suppressing activation of the mitogen-activated protein kinase (MAPK) signaling pathway, a key mediator of inflammatory amplification in AKI. Renal IRI was associated with robust MAPK activation and increased expression of pro-inflammatory mediators, whereas GPX3 overexpression significantly attenuated MAPK signaling and downstream inflammatory responses.
In addition, the researchers identify NADPH oxidase (NOX) as a critical downstream effector of GPX3-mediated protection. IRI-induced upregulation of NOX enzymes resulted in excessive reactive oxygen species production, exacerbating oxidative stress and inflammation. GPX3 markedly reduced NOX expression and ROS accumulation, thereby dampening oxidative injury. Importantly, pharmacological activation of MAPK signaling reversed the anti-inflammatory and antioxidant effects of GPX3, confirming that GPX3 functions through a MAPK–NOX regulatory axis.
Cell-based experiments further corroborated these findings, showing that GPX3 overexpression reduced hypoxia–reoxygenation–induced apoptosis and inflammatory cytokine release in renal tubular epithelial cells, while enhancing the expression of anti-inflammatory mediators.
Together, these results identify GPX3 as a key endogenous regulator of inflammatory and oxidative stress pathways in renal ischemia–reperfusion injury. By linking GPX3 to suppression of MAPK signaling and NADPH oxidase activity, this study provides new mechanistic insight into AKI pathogenesis and highlights GPX3 as a promising therapeutic target for preventing or mitigating renal injury in ischemic conditions.
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