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Syed Zaidi, Sudha Singh, Wendy Guzman, Shahid Husain; Regulation of acetylation and phosphorylation of STAT-3 by delta-opioid receptor (DOR) activation in glaucoma.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4955.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the role of acetylation and phosphorylation of STAT-3 during glaucoma progression and if it is regulated by DOR activation by SNC-121.
Intraocular pressure (IOP) was elevated by injecting 2M hypertonic saline into the limbal veins in the eyes of Brown Norway rats. Single-dose of DOR agonist, SNC-121 (i.p.; 1 mg/kg) was administered daily for 7 days post-injury. IOP was recorded weekly using a calibrated Tonolab tonometer. Pattern electroretinograms (ERGs) and optokinetic responses (OKR) were measured at day 42nd, post-injury. Retinas (n=4-6 per group) were collected at day 7th and 42nd and changes in the acetylation and phosphorylation of STAT-3 were determined by Western blotting and immunohistochemistry. Quantitative RT-PCR was used to measure the changes in gene expression of HK-2, GLUT-1, IL-1β, and IL-6.
Increased expression of STAT-3 has been reported in glaucoma, but its role in pathogenesis remains unclear. In this study, we observed a significant increase in the mRNA levels of STAT-3 by 40 ± 5% (p<0.01) and 90 ± 20% (p<0.05) at day 7th and 42nd, respectively, in ocular hypertensive (OH) animals. We also found significant (p<0.05) deficits in retinal function measured by Pattern ERG and OKR at day 42nd, post-injury. In addition, we found an increased in the production of pro-inflammatory cytokines (e.g., IL-1β, IL-6) and metabolic genes (e.g., GLUT-1, HK-2) in OH animals. Interestingly, the administration of SNC-121 reduced the up-regulation of mRNA expression of STAT-3, pro-inflammatory cytokines, and metabolic genes in OH animals. In this study, we did not see changes in the acetylation of STAT-3 in naive, OH animals, or in SNC121 treated OH animals. In contrast, we found that phosphorylation of STAT-3 at Tyr 705 was significantly increased by 80.7 ± 15% (p<0.05) and 92 ± 15% (p<0.05) at day 7th and 42nd, respectively, in OH animals, which was significantly blocked by SNC-121 treatment.
Our data provide solid clues for the first time that STAT3 phosphorylation at Tyr 705 plays a critical role in the glaucoma pathology. Based on our data, it is also evident that SNC-121 induced acetylation, in general, is neuroprotective and does not play any role in STAT3 mediated regulation of pro-inflammatory cytokines and metabolic genes.
This is a 2020 ARVO Annual Meeting abstract.
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