Inhibition of Stat3 by a Small Molecule Inhibitor Slows Vision Loss in a Rat Model of Diabetic Retinopathy

Vanlandingham, Phillip A.; Nuno, Didier; Quiambao, Alexander B.; Phelps, Eric; Wassel, Ronald A.; Ma, Jian-Xing; Farjo, Krysten M.; Farjo, Rafal

doi:10.1167/iovs.16-20641

Cited by 17 publications

(11 citation statements)

References 67 publications

(85 reference statements)

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“…Moreover, Xu et al demonstrated that STAT3 is up-regulated in DR-affected tissues and primary retinal vascular endothelial cells under high glucose (HG) conditions [39]. Increasing studies also showed that STAT3 could influence endothelial function in DR [40,41]. The results of our study also revealed that STAT3 expression was significantly increased in HG-treated ARPE-19 cells, which was obviously decreased after PG treatment.…”

Section: Discussionsupporting

confidence: 65%

RETRACTED ATICLE: Physcion 8-O-β-glucopyranoside exerts protective roles in high glucose-induced diabetic retinopathy via regulating lncRNA NORAD/miR-125/STAT3 signalling

Wan

Long

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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2020) Physcion 8-O-β-glucopyranoside exerts protective roles in high glucose-induced diabetic retinopathy via regulating lncRNA NORAD/miR-125/ STAT3 signalling, Artificial ABSTRACT Diabetic retinopathy (DR) is the leading cause of decreased vision and blindness globally. The aim of this study was to understand the role of physcion 8-O-b-glucopyranoside (PG) in high glucose (HG)induced DR and to investigate whether lncRNA NORAD/miR-125/STAT3 signalling was the underlying mechanism involved in DR. To this end, the serum levels of NORAD, miR-125, and STAT3 were determined in patients with DR. The APRE-19 cells were subjected to HG treatment to construct the cell model of DR. HG-disposed APRE-19 cell injury was assessed by detecting cell viability, apoptosis, concentrations of pro-inflammatory cytokines including TNF-a and IL-1b, and ROS generation. Moreover, the effect of PG on HG-disposed APRE-19 cell injury was investigated. NORAD was then overexpressed to investigate the combined effects of NORAD overexpression and PG on HG-disposed APRE-19 cell injury. Furthermore, the regulatory relationship between NORAD and miR-125 as well as miR-125 and STAT3 was investigated. The expression levels of NORAD and STAT3 were significantly increased in the serum of DR patients, while the miR-125 expression was decreased. The HG treatment-induced injury to APRE-19 cells, which were alleviated by PG treatment. Moreover, PG alleviated HG-disposed injury to ARPE-19 cells by decreasing NORAD. NORAD negatively regulated miR-125 expression and the combined effects of NORAD and PG on HG-disposed ARPE-19 cell injury were reversed by miR-125 overexpression. Furthermore, STAT3 was confirmed as a target gene of miR-125. Our results show that PG exerts protective roles in HG-disposed DR via regulating lncRNA NORAD/miR-125/STAT3 signalling. NORAD/miR-125/STAT3 axis may provide a novel perspective for target therapy of DR. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 65%

RETRACTED ATICLE: Physcion 8-O-β-glucopyranoside exerts protective roles in high glucose-induced diabetic retinopathy via regulating lncRNA NORAD/miR-125/STAT3 signalling

Wan

Long

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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“…We utilized STZ-diabetic rat models, which develop robust retinal neurodegeneration [20], to assess neuroprotective effects of PPARα activation in DR. We used optokinetic tracking to demonstrate that visual acuity, as detected by spatial frequency threshold [21], significantly decreased in diabetic rats and 8 and 12 weeks diabetic (p ≤ 0.001), and was partially restored by continuous oral treatment with PPARα agonist fenofibrate (p ≤ 0.05) (Fig 1A and 1B) . Fenofibrate did not affect visual acuity in non-diabetic rats.…”

Section: Resultsmentioning

confidence: 99%

“…We postulate that this seeming discrepancy could be because factors other than neurodegeneration contribute to optokinetic reflex in DR, and/or because mechanisms unrelated to PPARα affect long-term visual function. The optokinetic reflex declines in DR due to both neurodegeneration and unrelated pathologies such as increased cataract formation in DR and impaired reaction time in diabetic animals [21]. To our knowledge PPARα does not affect cataract formation or reaction time in diabetes, so the readout of neuroprotection in fenofibrate-treated diabetic animals may be precluded in part by these unrelated pathologies.…”

Section: Discussionmentioning

confidence: 99%

“…For visual acuity studies, STZ brown Norway rats were used to evaluate whether PPARα activation preserved visual acuity, as indicated by the optokinetic reflex. We selected this model because diabetic brown Norway rats reliably develop a robust decline in the optokinetic reflex by week 8 of DR [21]. We therefore measured the optokinetic reflex at weeks 8 and 12 of DR. Contrastingly, optokinetic tracking has not been used to assess visual acuity in STZ mice, and cannot be used in albino animals, which lack the optokinetic reflex.…”

Section: Methodsmentioning

confidence: 99%

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Neuroprotective effects of PPARα in retinopathy of type 1 diabetes

et al. 2019

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Diabetic retinopathy (DR) is a common neurovascular complication of type 1 diabetes. Current therapeutics target neovascularization characteristic of end-stage disease, but are associated with significant adverse effects. Targeting early events of DR such as neurodegeneration may lead to safer and more effective approaches to treatment. Two independent prospective clinical trials unexpectedly identified that the PPARα agonist fenofibrate had unprecedented therapeutic effects in DR, but gave little insight into the physiological and molecular mechanisms of action. The objective of the present study was to evaluate potential neuroprotective effects of PPARα in DR, and subsequently to identify the responsible mechanism of action. Here we reveal that activation of PPARα had a robust protective effect on retinal function as shown by Optokinetic tracking in a rat model of type 1 diabetes, and also decreased retinal cell death, as demonstrated by a DNA fragmentation ELISA. Further, PPARα ablation exacerbated diabetes-induced decline of visual function as demonstrated by ERG analysis. We further found that PPARα improved mitochondrial efficiency in DR, and decreased ROS production and cell death in cultured retinal neurons. Oxidative stress biomarkers were elevated in diabetic Pparα-/- mice, suggesting increased oxidative stress. Mitochondrially mediated apoptosis and oxidative stress secondary to mitochondrial dysfunction contribute to neurodegeneration in DR. Taken together, these findings identify a robust neuroprotective effect for PPARα in DR, which may be due to improved mitochondrial function and subsequent alleviation of energetic deficits, oxidative stress and mitochondrially mediated apoptosis.

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“…STAT3 factors influence endothelial function in DR [34,35]. Thus, we focused on the relationship between O-GlcNAcylation and STAT3 phosphorylation, and changes to specific STAT3 sites under different O-GlcNAcylation levels.…”

Section: Discussionmentioning

confidence: 99%

Identification of O-GlcNAcylation Modification in Diabetic Retinopathy and Crosstalk with Phosphorylation of STAT3 in Retina Vascular Endothelium Cells

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recently, we observed an increase in O-GlcNAc (O-linked-ß-N-acetylglucosamine) modification, and signal transducer and activator of transcription proteins 3 (STAT3) expression in primary retinal vascular endothelial cells (RVECs) under high glucose conditions and tissues altered by diabetic retinopathy (DR). In this study, we focused on the correlations between O-GlcNAcylation and STAT3 phosphorylation, and their potential effects with regards to DR. Methods: Expression of O-GlcNAcylation and STAT3 were detected in DR-affected tissues and primary RVECs. The relationship between O-GlcNAcylation and STAT3 was further delineated by immunoprecipitation and Western blot analysis. Effects of O-GlcNAcylation on human RVEC apoptosis and involved protein expression were assayed with flow cytometry and Western blot. Results: Global O-GlcNAcylation and pSTAT3 levels were significantly elevated in diabetic rat retina and primary RVECs under high glucose conditions. In vitro assays demonstrated that the Tyr705 site was sensitive to high glucose. While O-GlcNAcylation inhibited p727STAT3 expression, augmented O-GlcNAcylation could balance p705STAT3 expression within relatively high levels corresponding to vascular endothelial growth factor (VEGF) changes. Immunoprecipitation revealed that STAT3 was modified by O-GlcNAcylation and phosphorylation simultaneously. Next, we observed that overexpression of O-GlcNAcylation could relieve human RVEC apoptosis related to the JAK2-Tyr705STAT3-VEGF pathway. Conclusion: O-GlcNAcylation could relieve RVECs apoptosis through the STAT3 pathway in DR, and O-GlcNAcylation combined with STAT3 phosphorylation might open up new insights into the mechanisms of DR and other diabetic complications.

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Inhibition of Stat3 by a Small Molecule Inhibitor Slows Vision Loss in a Rat Model of Diabetic Retinopathy

Cited by 17 publications

References 67 publications

RETRACTED ATICLE: Physcion 8-O-β-glucopyranoside exerts protective roles in high glucose-induced diabetic retinopathy via regulating lncRNA NORAD/miR-125/STAT3 signalling

RETRACTED ATICLE: Physcion 8-O-β-glucopyranoside exerts protective roles in high glucose-induced diabetic retinopathy via regulating lncRNA NORAD/miR-125/STAT3 signalling

Neuroprotective effects of PPARα in retinopathy of type 1 diabetes

Identification of O-GlcNAcylation Modification in Diabetic Retinopathy and Crosstalk with Phosphorylation of STAT3 in Retina Vascular Endothelium Cells

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