April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
A fragment of netrin-1 is implicated in the induction of permeability in diabetic retinopathy
Author Affiliations & Notes
  • Khalil Miloudi
    Neurology, McGill University, Montreal, QC, Canada
  • Sarah Genest-Brunetta
    Biochemistry, University of Montreal, Montreal, QC, Canada
  • Francois Binet
    Medical biochemistry, Uppsala University, Uppsala, Sweden
  • Gaelle-Stephanie Mawambo-Tagne
    Biochemistry, University of Montreal, Montreal, QC, Canada
  • Agustin Cerani
    Biochemistry, University of Montreal, Montreal, QC, Canada
  • Agnieszka Dejda
    Biochemistry, University of Montreal, Montreal, QC, Canada
  • Flavio Rezende
    Ophtalmology, University of Montreal, Montreal, QC, Canada
  • Timothy Kennedy
    Neurology, McGill University, Montreal, QC, Canada
  • Przemyslaw Sapieha
    Ophtalmology, University of Montreal, Montreal, QC, Canada
  • Footnotes
    Commercial Relationships Khalil Miloudi, None; Sarah Genest-Brunetta, None; Francois Binet, None; Gaelle-Stephanie Mawambo-Tagne, None; Agustin Cerani, None; Agnieszka Dejda, None; Flavio Rezende, None; Timothy Kennedy, None; Przemyslaw Sapieha, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 412. doi:
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      Khalil Miloudi, Sarah Genest-Brunetta, Francois Binet, Gaelle-Stephanie Mawambo-Tagne, Agustin Cerani, Agnieszka Dejda, Flavio Rezende, Timothy Kennedy, Przemyslaw Sapieha; A fragment of netrin-1 is implicated in the induction of permeability in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):412.

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

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Abstract

Purpose: Although elevated VEGF is frequently associated with breakdown in barrier function in diabetic retinopathy (DR), we have recently described roles for neuronal guidance cues in the pathogenesis of DR. Here we described a new role for a fragment of netrin-1, the VI-V peptide fragment of netrin-1, in the development of DR-associated breakdown of barrier function.

Methods: We first investigated retinal levels of full-length and fragmented netrin-1 by Western Blot in early stages of DR in a streptozotocin-induced model of diabetes. In a modified version of the in vivo Miles Assay, we i) subcutaneously and ii) intraviteously injected recombinant netrin-1 or the shorter VI-V netrin-1 peptide into wild type mice at 10 weeks of age. A blue dye (Evans blue (EB)), was later injected intravenously. Permeability was then evaluated by i) measuring dorsal spots of subcutaneous leaking EB, and ii) by quantifying EB in retinas after overnight extraction in formamide. To identify possible signaling pathways involved, human retinal microvascular endothelial cells were similarly stimulated in vitro.

Results: Our findings reveal a significant increase in the levels of fragmented netrin-1 at 4 and 8 weeks in diabetic retinas. Intravitreal injection of the netrin-1 VI-V peptide significantly increased vascular permeability in vivo both in retina and after subcutaneous injection, when compared to full-length netrin-1 or vehicle. In agreement, in vitro data confirmed that the VI-V fragment of netrin-1 provoked the phosphorylation of permeability-associated pathways such FAK, Src, and VE-Cadherin.

Conclusions: These results show a new mechanism implicating a wider spatial effect of netrin-1 via the VI-V peptide fragment. Current studies aim to elucidate the cellular and molecular mechanism by which this recently described fragment may be implicated in the pathogenesis of DR.

Keywords: 690 retina: neurochemistry • 499 diabetic retinopathy • 531 ganglion cells  
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