Role of Glutaredoxin 2 (Grx2) in protecting the retina from light-induced damage

Purpose: Glutaredoxin 2 (Grx2), a glutathione-dependent oxidoreductase, is known to repair oxidative damage of protein thiol groups and also serve as electron donors for ribonucleotide reductase. Grx2 is highly expressed in tissues with high energy demand like heart, brain, liver, and kidney. Our previous study has shown that Grx2 is highly expressed in the neural retina where its physiological functions remain completely unknown. In this study, we evaluated the role of Grx2 in protecting the retina from light-induced damage by using Grx2 gene knockout (KO) mice as a model. Methods: Wild type (WT) and Grx2 KO mice were exposed to white light at 12,000 lux for 1 hour after dark adaptation. The retinal damage was evaluated by the electroretinogram (ERG) recording, spectral domain optical coherence tomography (SD-OCT) measurement, and fundus examination. Hematoxylin and Eosin (H&E) staining was used to analyze the morphological changes in the retina. To better understand the molecular basis of how Grx2 protects the retina from light induced damage, we performed the whole transcriptome shotgun sequencing (RNA-seq) to analyze the full transcriptome of the retinal tissue in light-exposed Grx2 KO mice. The gene network was explored using DESeq2 pathway analysis software. The selected genes of interest were further confirmed by real-time PCR and Western Blot. Results: Light-exposed Grx2 KO mice showed severe loss of both a- and b-wave amplitudes and the outer nuclear layer (ONL) in the Grx2 deficient mice was significantly thinner compared to that of light-exposed WT mice. We identified thousands of genes with statistical significant expression changes and classified them into cellular processes and molecular pathways. Interestingly, assessment of gene expression profile indicated that several nuclear factor erythroid 2 (Nrf2) regulated antioxidant genes including SOD1, NQO1, and catalase were dysregulated in Grx2 KO mice, which indicated that Grx2 may be a novel regulator of the Nrf2 defense pathway. Conclusions: Our results suggest that Grx2 may protect the retina from light-induced retinal degeneration. The protective effects of Grx2 in the retina may be explained at least in part by its ability to control the Nrf2 signaling pathway.