June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Hyperglycemia-driven dysregulation of Sp1 transcription factor in retinal cells
Author Affiliations & Notes
  • Kelly Donovan
    Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States
  • Oleg Alekseev
    Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States
  • Jane Clifford
    Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Kelly Donovan, None; Oleg Alekseev, None; Jane Clifford, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2505. doi:
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      Kelly Donovan, Oleg Alekseev, Jane Clifford; Hyperglycemia-driven dysregulation of Sp1 transcription factor in retinal cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2505.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The molecular etiology of early pathologic changes in the diabetic retina is incompletely characterized. Transcription factor specificity protein 1 (Sp1) exhibits pathologic transcriptional activity in multiple diabetic tissues, and directly upregulates pro-angiogenic and pro-fibrotic factors in retinal cells. We investigated mechanisms of hyperglycemia-driven Sp1 dysfunction, focusing on the von Hippel Lindau (VHL) protein.

Methods : ARPE-19 (human retinal pigment epithelial) and MIOM1 (human Müller) cells were used to quantify changes in protein-protein interaction by co-immunoprecipitation. Changes in RNA and protein were evaluated by RT-qPCR and Western blot, respectively. Luminometer was used to analyze luciferase activity.

Results : Sp1 is negatively regulated by interaction with the von Hippel Lindau (VHL) protein. We have discovered that hyperglycemia significantly decreases Sp1 interaction with the VHL in both ARPE-19 and MIOM1 cells. Reciprocal co-immunoprecipitation suggests that VHL may be post-translationally modified by the glucose-derived carbohydrate O-GlcNAc, which has not been previously reported. Sp1-mediated transcription is modulated by VHL in ARPE-19 and MIOM1 cells.

Conclusions : VHL has not previously been implicated in the pathogenesis of diabetic retinopathy. Preliminary evidence suggests that negative regulation of Sp1 may be impacted by hyperglycemia. Sp1 is widely shown to have increased transcriptional activity in diabetic tissues. These data reveal a potential new mechanism of pathologic Sp1 transcriptional activity in hyperglycemic retinal cells.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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