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. 2023 Feb 15;133(4):e165654. doi: 10.1172/JCI165654

Figure 1. Changes of endothelial cells in diabetes.

Figure 1

(Left) Early DKD is characterized by increased VEGFA expression, VEGFA released by podocytes binds to VEGFR receptors (VEGFR1/2) expressed on glomerular endothelial cells. In addition, VEGFA may also affect the balance between the production of the vasoconstrictive factor endothelin-1 (ET-1) and the vasodilatory factor nitric oxide (NO). By binding to its receptors VEGFR1 and VEGFR2 on GEnCs, VEGFA can stimulate NO production and inhibit ET-1 expression, thus exerting protective effects on the glomerulus. Glomerular endothelial cells release endothelin, which can signal to nearby endothelial cells via endothelin receptors (ETRs). LRG1 potentiates TGFβ signaling to activate Smad pathways in endothelial cells. All 3 signals shown in this cell induce proliferation, migration, and/or angiogenesis in endothelial cells in the DKD glomerulus. (Right) Elevated glucose levels and dysregulated insulin signaling promote increased mitochondrial reactive oxygen species (ROS) levels. Nitric oxide can react with endothelial ROS to release peroxynitrates (ONOO-). Increased oxidative stress will lead to apoptosis of glomerular endothelial cells and enhanced endothelial permeability — changes mostly observed in late DKD. IR, insulin receptor; TGFβR, TGFβ receptor; GLUT4, insulin sensitive glucose transporter 4.