Reduced β2GPI Inhibiting Glomerular Mesangial Cells VEGF-NO Axis Uncoupling Induced by High Glucose

Abstract

VEGF-NO axis uncoupling is an important pathogenesis for DN. Reduced β2GPI could play a part in VEGF signaling pathway and has a protective effect on diabetic vascular disease. This study investigates the effect of reduced β2GPI on glomerular mesangial cells VEGF-NO axis uncoupling induced by high glucose. Compared to control group, glomerular mesangial cell line HBZY-1 cells treated with high glucose expressed higher levels of VEGF mRNA and protein and produced more ROS but less NO. The related proteins related to VEGF-NO axis were assayed. High glucose could significantly increase the expression of the level of VEGFR2 and obviously increase phosphorylation of Akt and eNOS but significantly decrease the expression of GTP cyclohydrolase 1 (GCH-1), reducing the production of eNOS dimer. Both β2GPI and reduced β2GPI partly reverse these effects caused by high glucose. Reduced β2GPI had stronger effect than β2GPI. GCH-1 is the speed limit of tetrahydrobiopterin (BH4) synthesis enzyme. As the key part of eNOS cofactors, BH4 could partly restore eNOS dimer induced by high glucose. Our results indicated that high glucose could interfere with eNOS dimer formation. β2GPI and reduced β2GPI can partly reverse the VEGF-NO axis uncoupling by restoring the GCH-1 expression level and then promote eNOS dimer formation.

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

“…On the contrary, ECs proliferation in response to VEGF-A can be prevented by using an NO donor ( Nakagawa et al, 2006 ). Furthermore, recent studies have demonstrated that partial reversion of uncoupling of VEGF-A with NO can improve endothelial dysfunction induced by high glucose in type 2 diabetic rats ( Hou et al, 2014 ; Zhou et al, 2018 ). In total, current data suggests that the reduced NO bioavailability in diabetic kidney can further enhance VEGF-A/VEGFR2 signaling and subsequently induce more severely aberrant angiogenesis.…”