O-GlcNAcylation of FoxO1 mediates nucleoside diphosphate kinase B deficiency induced endothelial damage

• Verfasst von: Shan, Shenliang [VerfasserIn]
• Verfasst von: Chatterjee, Anupriya [VerfasserIn]
• Verfasst von: Qiu, Yi [VerfasserIn]
• Verfasst von: Hammes, Hans-Peter [VerfasserIn]
• Verfasst von: Wieland, Thomas [VerfasserIn]
• Verfasst von: Feng, Yuxi [VerfasserIn]
• Titel: O-GlcNAcylation of FoxO1 mediates nucleoside diphosphate kinase B deficiency induced endothelial damage
• Verf.angabe: Shenliang Shan, Anupriya Chatterjee, Yi Qiu, Hans-Peter Hammes, Thomas Wieland & Yuxi Feng
• E-Jahr: 2018
• Jahr: 12 July 2018
• Fussnoten: Gesehen am 04.09.2018
• Titel Quelle: Enthalten in: Scientific reports
• Ort Quelle: [London] : Springer Nature, 2011
• Jahr Quelle: 2018
• Band/Heft Quelle: 8(2018) Artikel-Nummer 10581, 14 Seiten
• ISSN Quelle: 2045-2322
• DOI: doi:10.1038/s41598-018-28892-y
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1580676383
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

Nucleoside diphosphate kinase B (NDPK-B) acts as a protective factor in the retinal vasculature. NDPK-B deficiency leads to retinal vasoregression mimicking diabetic retinopathy (DR). Angiopoetin 2 (Ang-2), an initiator of retinal vasoregression in DR, is upregulated in NDPK-B deficient retinas and in NDPK-B depleted endothelial cells (ECs) in vitro. We therefore investigated the importance of Ang-2 in NDPK-B deficient retinas and characterized the mechanisms of Ang-2 upregulation upon NDPK-B depletion in cultured ECs. The crucial role of retinal Ang-2 in the initiation of vasoregression was verified by crossing NDPK-B deficient with Ang-2 haplodeficient mice. On the molecular level, FoxO1, a transcription factor regulating Ang-2, was upregulated in NDPK-B depleted ECs. Knockdown of FoxO1 abolished the elevation of Ang-2 induced by NDPK-B depletion. Furthermore O-GlcNAcylated FoxO1 was found preferentially in the nucleus. An increased O-GlcNAcylation of FoxO1 was revealed upon NDPK-B depletion. In accordance, the inhibition of protein O-GlcNAcylation normalized NDPK-B depletion induced Ang-2 upregulation. In summary, we demonstrated that the upregulation of Ang-2 upon NDPK-B deficiency is driven by O-GlcNAcylation of FoxO1. Our data provide evidence for a central role of protein O-GlcNAcylation in NDPK-B associated vascular damage and point to the hexosamine pathway as an important target in retinal vasoregression.