Glutaredoxin 2 (Grx2) protects the retina from light-induced photoreceptor damage via regulating the endothelin receptor B (Ednrb) pathway

Abstract

Purpose : Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase which is known to reduce S-glutathionylated proteins. In a previous study, we have found that Grx2 could protect the retina from light-induced retinal degeneration. To better understand the protective effects of Grx2 in the retina, our study was thus extended to analyze the full transcriptome changes of the retinal tissue in light-exposed Grx2 knockout (KO) mice.

Methods : Wild-type (WT) and Grx2 KO mice were exposed to white light at 23,000 lux for 1 hour after dark adaptation for 10 hours. The retinal damage was confirmed by the electroretinogram (ERG) recording and spectral domain optical coherence tomography (SD-OCT) measurement. Protein glutathionylation level was evaluated by Western Blot. We then compared the full transcriptome of the retinal tissue in WT and Grx2 KO mice using transcriptome shotgun sequencing (RNA-seq). The gene network was analyzed using DESeq2 pathway analysis software, and real-time PCR and Western Blot were used to confirm the selected genes of interest.

Results : Light-exposed Grx2 KO mice showed a compromised visual function as indicated by severe loss of both a- and b-wave amplitudes and the thinning of the outer nuclear layer (ONL). Protein glutathionylation level was elevated in light-exposed Grx2 KO mice. We identified thousands of genes with statistically significant expression changes in light-exposed Grx2 KO mice and classified them into cellular processes and molecular pathways. Among these pathways, many genes that are related to complement activation, inflammation, and cell survival system were significantly upregulated. These genes include Bcl-3 and Fgf2 in NF-KappaB family pathway, C4b in classical activation pathway, Jak3 and STAT3 in JAK-STAT signaling pathway, Cdkn1a in DNA damage response pathway, and endothelin 2 (Edn2) and endothelin receptor B (Ednrb) in the endothelin signaling pathway. Among these genes of interest, we found light damaged Grx2 KO mice showed significantly higher expressions of Ednrb and Edn2, in both mRNA and protein levels than their WT littermates.

Conclusions : Collectively, our results suggest that Grx2 could protect the retina from light-induced retinal degeneration. Grx2 may play an important role in protecting the retina from light-induced photoreceptor damage by regulating Ednrb-mediated pathway.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.