Slit2-Robo Signaling Pathway as a Potential Target for Attenuating Pathological Diabetic Glomerular Angiogenesis

A hallmark of diabetes, the leading cause of kidney failure, is glomerular endothelial cell injury, where pathological angiogenesis contributes to hyperfiltration, a common feature linked to progression of renal injury. No clinically available therapies safely target this process. Slit2 has emerged as a regulator of endothelial function, eliciting either pro- or anti-angiogenic effects through its Robo1 and Robo4 receptors respectively. Glomerular endothelial cells grown in high glucose medium expressed lower levels of Robo4, but not Robo1, and had greater response to vascular endothelial growth factor, while Robo1 knockdown inhibited VEGF-induced tube formation and migration. While healthy glomerular endothelial cell expressed high levels of Robo4 and low levels of Robo1 in vivo, Robo4 levels fell while Robo1 did not significantly change. Four weeks post-streptozotocin-induced diabetes, Robo4 knockout mice kidneys demonstrated increased glomerular endothelial cell density. Our observations suggest that diabetic glomerular angiogenesis is promoted by a reduction in anti-angiogenic Slit2-Robo4 activity.M.Sc