Neuropilin Expression in Podocytes: The Implications for SEMA3 Anti-Cancer Therapy

Neuropilins (Nrp) are transmembrane receptors in endothelial and carcinoma cells that bind to angiogenic ligands including vascular endothelial growth factor (VEGF) to promote neovascularization, the sprouting of new blood capillaries providing oxygen and nutrients to the tumor. Additionally, Nrp binds to an alternate family of proteins, Class 3 Semaphorins (SEMA3), which compete with VEGF and inhibit angiogenesis. Targeting of either Nrp1 or Nrp2 with neutralizing antibodies or with exogenous SEMA3 proteins has successfully inhibited cancer progression in preclinical trials. Our goal was to investigate the expression, localization and function of Nrps within the kidney to examine potential therapeutic off-target effects. We hypothesized that podocytes express Nrp1 but not Nrp2 and that the Nrp1 ligand, SEMA3A, would induce proteinuria while the Nrp2 ligand, SEMA3F, would not. Using immunoblotting, immunohistochemistry and X-gal staining of kidneys from wildtype (Nrp2+/+) and transgenic mice (Nrp2+/lacz, ...