Diabetes-Induced Impairments in Robo Signalling Augment Glomerular Angiogenesis

Diabetic glomerular angiogenesis represents an early form of diabetic kidney injury driven by VEGF. Robo1 and Robo4 are cell surface receptors that can regulate VEGF-mediated endothelial angiogenic activity. We have shown previously that glomerular endothelial Robo4 expression is downregulated with high glucose exposure, whereas Robo1 expression is unchanged and that Robo1 is essential for VEGF-induced angiogenic activity. In this thesis I aim to determine whether alterations in Robo2 and Robo4 levels regulate VEGF-induced glomerular angiogenesis in high glucose and diabetes. Robo4 deficiency was associated with augmented migration in vitro while Robo2 did not change with high glucose or diabetes exposure. Robo4 KO mice exhibited increased PECAM-1 density, glomerular capillary length, and creatinine clearance after 5 weeks of STZ-induced diabetes. Our observations suggest that diabetic glomerular angiogenesis is driven by enhanced glomerular endothelial VEGF responsiveness promoted by a shift in Robo signalling, favouring more pro-angiogenic Robo1, and less anti-angiogenic Robo4 activity.M.Sc.2021-11-28 00:00:0