Phosphorylation of Dab2 is involved in inhibited VEGF-VEGFR-2 signaling induced by downregulation of syndecan-1 in glomerular endothelial cell.

Disabled-2 (Dab2) and PAR-3 (partitioning defective 3) are reported to play critical roles in maintaining retinal microvascular endothelial cells biology by regulating VEGF-VEGFR-2 signaling. The role of Dab2 and PAR-3 in glomerular endothelial cell (GEnC) is unclear. In this study, we found that, no matter whether with vascular endothelial growth factor (VEGF) treatment or not, decreased expression of Dab2 could lead to cell apoptosis by preventing activation of VEGF-VEGFR-2 signaling in GEnC, accompanied by reduced membrane VEGFR-2 expression. And silencing of PAR-3 gene expression caused increased apoptosis of GEnC by inhibiting activation of VEGF-VEGFR-2 signaling and membrane VEGFR-2 expression. In our previous research, we found that the silencing of syndecan-1 gene expression inhibited VEGF-VEGFR-2 signaling by modulating internalization of VEGFR-2. And our further research demonstrated that downregulation of syndecan-1 lead to no significant change in the expression of Dab2 and PAR-3 both at messenger RNA and protein levels in GEnC, while phosphorylation of Dab2 was significantly increased in GEnC transfected with Dab2 small interfering RNA (siRNA) compared with control siRNA. Atypical protein kinase C could induce phosphorylation of Dab2, thus negatively regulating VEGF-VEGFR-2 signaling. And we found that decreased expression of syndecan-1 lead to activation of and inhibitor treatment could block phosphorylation of Dab2 in GEnC. Besides, aduanyu1531 inhibitor treatment could activate VEGF-VGEFR-2 signaling in GEnC transfected with syndecan-1 siRNA in a dose-dependent manner. In conclusion, we speculated that phosphorylation of Dab2 is involved in preventing activation of VEGF-VEGFR-2 signaling in GEnC transfected with syndecan-1 siRNA. This provides a new target for the therapy of GEnC injury and kidney disease.

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