The retinal tyrosine kinome of diabetic Akimba mice highlights potential for specific SRC family kinase inhibition in retinal vascular disease

Jurgen Sergeys, Inge Van Hove, Tjing-tjing Hu, Carolin Temps, Neil O. Carragher, Asier Unciti-broceta, Jean H.m. Feyen, Lieve Moons, Michael Porcu

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Although anti-VEGF therapies have radically changed clinical practice, there is still an urgent demand for novel, integrative approaches for sight-threatening retinal vascular diseases. As we hypothesize that protein tyrosine kinases are key signaling mediators in retinal vascular disease, we performed a comprehensive activity-based tyrosine kinome profiling on retinal tissue of 12-week old Akimba mice, a translational model displaying hallmarks of early and advanced diabetic retinopathy. Western blotting was used to confirm retinal tyrosine kinase activity in Akimba mice. HUVEC tube formation and murine organotypic choroidal sprouting assays were applied to compare tyrosine kinase inhibitors with different specificity profiles. HUVEC toxicity and proliferation were evaluated using the CellTox™ Green Cytotoxicity and PrestoBlue™ Assays. Our results indicate a shift of the Akimba retinal tyrosine kinome towards a hyperactive state. Functional network analysis of significantly hyperphosphorylated peptides and upstream kinase prediction revealed a central role for Src-FAK family kinases. Western blotting confirmed hyperactivity of this signaling node in the retina of Akimba mice. We demonstrated that not only Src but also FAK family kinase inhibitors with different selectivity profiles were able to suppress angiogenesis in vitro and ex vivo. In the latter model, the novel selective Src family kinase inhibitor eCF506 was able to achieve potent reduction of angiogenesis, comparable to the less specific inhibitor Dasatinib. None of the tested compounds demonstrated acute endothelial cell toxicity. Overall, the collected findings provide the first comprehensive overview of retinal tyrosine kinome changes in the Akimba model of diabetic retinopathy and for the first time highlight Src family kinase inhibition using highly specific inhibitors as an attractive therapeutic intervention for retinal vascular pathology
Original languageEnglish
Pages (from-to)108108
JournalExperimental Eye Research
Early online date23 Jun 2020
DOIs
Publication statusE-pub ahead of print - 23 Jun 2020

Keywords / Materials (for Non-textual outputs)

  • Akimba mouse
  • Vascular pathology
  • Src
  • FAK
  • Retina
  • Kinase profiling
  • Diabetic retinopathy

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