Induction of Podocyte VEGF164 Overexpression at Different Stages of Development Causes Congenital Nephrosis or Steroid-Resistant Nephrotic Syndrome

The tight regulation of vascular endothelial growth factor-A (VEGF-A) signaling is required for both the development and maintenance of the glomerular filtration barrier, but the pathogenic role of excessive amounts of VEGF-A detected in multiple renal diseases remains poorly defined. We generated inducible transgenic mice that overexpress podocyte VEGF(164) at any chosen stage of development. In this study, we report the phenotypes that result from podocyte VEGF(164) excess during organogenesis and after birth. On doxycycline induction, podocin-rtTA: tet-O-VEGF(164) mice express twofold higher kidney VEGF(164) levels than single transgenic mice, localized to podocytes. Podocyte VEGF(164) overexpression during organogenesis resulted in albuminuria at birth and was associated with glomerulomegaly, uniform podocyte effacement, very few and wide foot processes joined by occluding junctions, almost complete absence of slit diaphragms, and swollen endothelial cells with few fenestrae as revealed by transmission electron microscopy. Podocyte VEGF(164) overexpression after birth caused massive albuminuria in 70% of 2-week-old mice, glomerulomegaly, and minimal changes on light microscopy. Transmission electron microscopy showed podocyte effacement and fusion and morphologically normal endothelial cells. Podocyte VEGF(164) overexpression induced nephrin down-regulation without podocyte loss. VEGF(164)-induced abnormalities were reversible on removal of doxycycline and were unresponsive to methylprednisolone. Collectively, the data suggest that moderate podocyte VEGF(164) overexpression during organogenesis results in congenital nephrotic syndrome, whereas VEGF(164) overexpression after birth induces a steroid-resistant minimal change like-disease in mice. (Am J pathol 2010, 177:2225-2233: DOI: 10.2353/ajpath.2010.091146)