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.
Highlights
Nucleoside diphosphate kinase B (NDPK-B) catalyzes the conversion of nucleoside diphosphates to nucleoside triphosphates[1]
NDPK-B deficient retinas exhibited diabetic retinopathy (DR)-like pathology which is accompanied by an elevation of angiopoietin 2 (Ang-2)
Our study revealed that increased O-GlcNAcylation of FoxO1 and the subsequent upregulation of Ang-2 play a major role in mediating the biological effects of NDPK-B depletion in endothelial cells
Summary
Nucleoside diphosphate kinase B (NDPK-B) catalyzes the conversion of nucleoside diphosphates to nucleoside triphosphates[1]. NDPK-B deficient retinas showed a significant decrease in pericyte coverage and an increase in formation of acellular capillaries mimicking the pathology of early stage diabetic retinopathy (DR). Elevated levels of Ang-2 in the retina are a crucial factor in the induction of pericyte dropout, which leads to retinal vasoregression. Depletion of retinal Ang-2 reduced the hyperglycemia-induced pericyte dropout and formation of acellular capillaries[12,13]. We hypothesized that FoxO1, protein O-GlcNAcylation and Ang-2 might be mediators of the endothelial damage induced by NDPK-B deficiency. We provide evidence that the enhanced O-GlcNAcylation of FoxO1 after NDPK-B depletion is regulating its protein expression and thereby driving the upregulation of Ang-2 in endothelial cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
