Angiotensin-(1–7) attenuates protein O-GlcNAcylation in the retina by Epac/Rap1-dependent inhibition of O-GlcNAc transferase

Sadie K. Dierschke, Allyson L. Toro, Alistair J. Barber, Amy C. Arnold, Michael D. Dennis

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

PURPOSE. O-GlcNAcylation of cellular proteins contributes to the pathophysiology of diabetes and evidence supports a role for augmented O-GlcNAcylation in diabetic retinopathy. The aim of this study was to investigate the impact of the renin-angiotensin system on retinal protein O-GlcNAcylation. METHODS. Mice fed a high-fat diet were treated chronically with the angiotensin-converting enzyme inhibitor captopril or captopril plus the angiotensin-(1–7) Mas receptor antagonist A779. Western blotting and quantitative polymerase chain reaction were used to analyze retinal homogenates. Similar analyses were performed on lysates from human MIO-M1 retinal Müller cell cultures exposed to media supplemented with angiotensin-(1–7). Culture conditions were manipulated to influence the hexosamine biosynthetic pathway and/or signaling downstream of the Mas receptor. RESULTS. In the retina of mice fed a high-fat diet, captopril attenuated protein O-GlcNAcylation in a manner dependent on Mas receptor activation. In MIO-M1 cells, angiotensin-(1–7) or adenylate cyclase activation were sufficient to enhance cyclic AMP (cAMP) levels and inhibit O-GlcNAcylation. The repressive effect of cAMP on O-GlcNAcylation was dependent on exchange protein activated by cAMP (EPAC), but not protein kinase A, and was recapitulated by a constitutively active variant of the small GTPase Rap1. We provide evidence that cAMP and angiotensin-(1–7) act to suppress O-GlcNAcylation by inhibition of O-GlcNAc transferase (OGT) activity. In cells exposed to an O-GlcNAcase inhibitor or hyperglycemic culture conditions, mitochondrial superoxide levels were elevated; however, angiotensin-(1–7) signaling prevented the effect. CONCLUSIONS. Angiotensin-(1–7) inhibits retinal protein O-GlcNAcylation via an EPAC/Rap1/OGT signaling axis.

Original languageEnglish (US)
Article number24
JournalInvestigative Ophthalmology and Visual Science
Volume61
Issue number2
DOIs
StatePublished - Feb 2020

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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