Abstract
Genetic factors play an important role in the pathogenesis of diabetic retinopathy (DR). While many studies have focused on genes that increase susceptibility to DR, herein, we aimed to explore genes that confer DR resistance. Previously, we identified Hmg CoA reductase degradation protein 1 (SYVN1) as a putative DR protective gene via gene expression analysis. Transgenic mice overexpressing SYVN1 and wild-type (WT) mice with streptozotocin-induced diabetes were used in this experiment. Retinal damage and vascular leakage were investigated 6 months after induction of diabetes by histopathological and retinal cell apoptosis analyses and by retinal perfusion of fluorescein isothiocyanate-conjugated dextran. Compared with diabetic WT mice, diabetic SYVN1 mice had significantly more cells and reduced apoptosis in the retinal ganglion layer. Retinal vascular leakage was significantly lower in diabetic SYVN1 mice than in diabetic WT mice. The expression levels of endoplasmic reticulum (ER) stress-related, pro-inflammatory, and pro-angiogenic genes were also analyzed. Lower expression levels were observed in diabetic SYVN1 mice than in WT controls, suggesting that SYVN1 may play an important role in inhibiting ER stress, chronic inflammation, and vascular overgrowth associated with DR. Thus, these results strongly supported our hypothesis that SYVN1 confers DR resistance.
Highlights
A relatively unexplored, but important, area of research focuses on the role of genetic factors in maintaining good health
We were inspired by this idea and focused on the gene expression profiles of long-term diabetic patients who did not develop Diabetic retinopathy (DR)
Several previously published reports have demonstrated that ER stress has an important role in many diseases and signaling pathways[17,18,19,20,21]
Summary
We confirmed that CHOP and other ER stress factors played an important role in the development and progression of DR6. Differences in the gene expression of ER stress factors between hyperglycemic and normal mouse retinas were tested using real-time polymerase chain reaction (PCR) functional gene chips. The results indicated that multiple factors regulating ER-associated degradation (ERAD) were expressed at significantly lower levels in hyperglycemic mouse retinas than in control retinas[8]. We generated a transgenic mouse line that overexpresses SYVN1 and used these mice to study the protective role of SYVN1 against DR by inducing diabetes using streptozotocin (STZ) injection. We explored the mechanism of DR resistance in the SYVN1-overexpressing mice by analyzing three potential mechanisms, including inflammatory responses, ER stress pathway activation, and vascular growth factor expression
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