VEGF and podocytes in diabetic nephropathy

Abstract

Vascular endothelial growth factor-A (VEGF-A) is a protein secreted by podocytes that is necessary for survival of endothelial cells, podocytes, and mesangial cells. VEGF-A regulates slit-diaphragm signaling and podocyte shape via VEGF-receptor 2-nephrin-nck-actin interactions. Chronic hyperglycemia-induced excess podocyte VEGF-A and low endothelial nitric oxide drive the development and the progression of diabetic nephropathy. The abnormal cross-talk between VEGF-A and nitric oxide pathways is fueled by the diabetic milieu, resulting in increased oxidative stress. Recent findings on these pathogenic molecular mechanisms provide new potential targets for therapy for diabetic renal disease.

Figure 1. Expression of VEGFR2 in vivo

Transmission electron microscopy from Flk-1-LacZ kidney showing LacZ deposits en lieu of VEGFR2 localized to A) foot processes near slit-diaphragm, GBM and fenestrated endothelium; B) podocytes and endothelial cell. Scale bars= 200nm (A) and 1 μm (B). Sample processed as reported.

Figure 2. Pathways of VEGF-A increase in diabetes

Figure 3. Consequences of VEGF-A increase in diabetic nephropathy

VEGF-A increases TGFβ, CTGF and established a positive feedback loop, leading to extracellular matrix (ECM) accumulation and GBM thickening (orange); VEGF-A induces nephrin downregulation and foot process effacement (FPE) (green); VEGF-A stimulates eNOS, which in the setting of high ROS leads to peroxinitrite (ONOO⁻) and further ROS generation, a positive feedback loop (blue), the dashed line represents the normal negative feedback regulation of VEGF-A by NO, not operative in DN. Low NO and high ROS damage endothelial cells and induce HTN.

Figure 4

VEGF-induced thickening and distortion of podocyte foot processes in diabetic mice, observed by scanning electron microscopy. A) Control diabetic glomerulus; B) Vegf₁₆₄ overexpressing glomerulus showing wider foot processes. Scale bars=2 μm.