VEGF is a potent angiogenic and endothelial cell growth factor that is key for the development of the glomerulus, the main filtration unit of the kidney. It is continued to be expressed in the mature glomerulus, with podocytes being the major site of production. VEGF binds to two receptors, VEGFR-1 and VEGFR-2, which are expressed by the adjacent endothelial cells (ECs). VEGFR-2 is the primary mediator of VEGF signaling while VEGFR-1is thought to function as a ‘decoy’ receptor, sequestering VEGF away from VEGFR-2. Gene targeting studies in mice show that VEGF loss from the podocyte results in profound defects of the ECs, consistent with a paracrine signaling loop. However, the identification of VEGF receptors on podocytes in vitro suggests an additional autocrine signaling pathway for VEGF may exist. To further study the role of VEGF in the glomerulus and to address whether a VEGF autocrine loop is functional in vivo, we generated a transgenic mouse model with inducible VEGF upregulation in the podocyte and genetically deleted VEGFR-2 and VEGFR-1 from the podocyte using the Cre-loxP system. Increased VEGF production from the podocyte leads to increased glomerular permeability and ultrastructural changes in the glomerular filtration barrier depending on the time and length of induction. Podocyte-selective deletion of VEGFR-2 did not cause glomerular disease. In contrast, VEGFR-1 loss from the podocyte led to proteinuria and glomerular defects at 6 weeks of age with extensive podocyte foot process effacement. In keeping with the model that VEGFR-1 functions as a VEGF trap, similarities were observed between the glomerular lesions of VEGFR-1 mutant mice and transgenic mice that overexpress VEGF within podocytes. Strikingly, in vitro studies also revealed an increase in podocyte cell adhesion to sVEGFR-1, suggesting additional roles for sVEGFR-1. Together, these data suggest that a tight regulation of VEGF must be maintained in the adult glomerulus. Furthermore, these findings provide the first genetic evidence that VEGF autocrine signaling loop through VEGFR-2 is dispensable in normal glomeruli. In addition, podocytes express sVEGFR-1 and is required in podocytes in vivo to maintain glomerular integrity by regulating VEGF availability and podocyte cell adhesive properties.

VEGF is a potent angiogenic and endothelial cell growth factor that is key for the development of the glomerulus, the main filtration unit of the kidney. It is continued to be expressed in the mature glomerulus, with podocytes being the major site of production. VEGF binds to two receptors, VEGFR-1 and VEGFR-2, which are expressed by the adjacent endothelial cells (ECs). VEGFR-2 is the primary mediator of VEGF signaling while VEGFR-1is thought to function as a ‘decoy’ receptor, sequestering VEGF away from VEGFR-2. Gene targeting studies in mice show that VEGF loss from the podocyte results in profound defects of the ECs, consistent with a paracrine signaling loop. However, the identification of VEGF receptors on podocytes in vitro suggests an additional autocrine signaling pathway for VEGF may exist. To further study the role of VEGF in the glomerulus and to address whether a VEGF autocrine loop is functional in vivo, we generated a transgenic mouse model with inducible VEGF upregulation in the podocyte and genetically deleted VEGFR-2 and VEGFR-1 from the podocyte using the Cre-loxP system. Increased VEGF production from the podocyte leads to increased glomerular permeability and ultrastructural changes in the glomerular filtration barrier depending on the time and length of induction. Podocyte-selective deletion of VEGFR-2 did not cause glomerular disease. In contrast, VEGFR-1 loss from the podocyte led to proteinuria and glomerular defects at 6 weeks of age with extensive podocyte foot process effacement. In keeping with the model that VEGFR-1 functions as a VEGF trap, similarities were observed between the glomerular lesions of VEGFR-1 mutant mice and transgenic mice that overexpress VEGF within podocytes. Strikingly, in vitro studies also revealed an increase in podocyte cell adhesion to sVEGFR-1, suggesting additional roles for sVEGFR-1. Together, these data suggest that a tight regulation of VEGF must be maintained in the adult glomerulus. Furthermore, these findings provide the first genetic evidence that VEGF autocrine signaling loop through VEGFR-2 is dispensable in normal glomeruli. In addition, podocytes express sVEGFR-1 and is required in podocytes in vivo to maintain glomerular integrity by regulating VEGF availability and podocyte cell adhesive properties.