靶向血管生成素-1的上调可改善早期糖尿病性肾病

Authors

Luigi Gnudi MD, PhD

Vascular growth factors play an important role in maintaining the integrity of the glomerular filtration barrier. In healthy adult glomeruli the pro-endothelial survival factors vascular endothelial growth factor (VEGF)A and angiopoietin (Angpt)1 are constitutively expressed in glomerular podocyte epithelia. We demonstrated that in streptozotocin induced type-1 diabetic mice this milieu of vascular growth factors was altered with decreased Angpt1 expression VEGFA upregulation decreased soluble VEGFR1 (sVEGFR1) and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria nephromegaly hyperfiltration and glomerular ultrastructural alterations with aberrant angiogenesis. We hypothesised that if the expression of Angpt1 could be restored within the glomeruli manifestations of early diabetic glomerulopathy might be ameliorated. Podocyte-specific inducible Angpt1 upregulation in diabetic mice caused a 70% reduction of albuminuria and reduction in diabetes-induced glomerular endothelial cells proliferation; hyperfiltration and renal morphology were unchanged. High VEGF/VEGFR system activation and reduced eNOS activation and NO availability as seen in diabetes are implicated in glomerular permeability to protein. Angpt1 upregulation resulted in an increased Tie-2 phosphorylation and led to an increase in sVEGFR1 which was paralleled by a decrease in VEGFR2 phosphorylation; furthermore Angpt1 upregulation lead to a significant increase in eNOS activation as evidenced by increased eNOS-Ser1177 phosphorylation. Diabetes-induced nephrin phosphorylation known to result in changes in podocyte cytoskeleton and proteinuria was reduced in diabetic mice with Angpt1 upregulation. In conclusion a podocyte-specific increase of Angpt1 within diabetic glomeruli ameliorates VEGF signalling eNOS activation and inhibits nephrin phosphorylation resulting in improved glomerular permeability to protein.

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