Search

BACKGROUND: Vascular endothelial growth factor A (VEGF) is an essential growth factor during glomerular development and postnatal homeostasis. VEGF is secreted in high amounts by podocytes into the primary urine, back-filtered across the glomerular capillary wall to act on endothelial cells. So far it has been assumed that VEGF back-filtration is driven at a constant rate exclusively by diffusion. METHODS: In the present work, glomerular VEGF back-filtration was investigated in vivo using a novel extended model based on endothelial fenestrations as surrogate marker for local VEGF concentrations. Single nephron glomerular filtration rate (SNGFR) and/or local filtration flux were manipulated by partial renal mass ablation, tubular ablation, and in transgenic mouse models of systemic or podocytic VEGF overexpression or reduction. RESULTS: Our study shows positive correlations between VEGF back-filtration and SNGFR as well as effective filtration rate under physiological conditions along individual glomerular capillaries in rodents and humans. CONCLUSION: Our results suggest that an additional force drives VEGF back-filtration, potentially regulated by SNGFR.

Iyoda et al. have provided strong experimental evidence for beneficial effects of PDGF signalling inhibition in two seemingly unrelated glomerular diseases: rapidly progressive glomerulonephritis (RPGN) in the present study and focal and segmental glomerulosclerosis (FSGS) in a previous study. Novel insights into the pathogenesis of these two diseases have unravelled a common cellular mechanism: activation of parietal epithelial cells (PECs). In addition, recent studies have shown that PDGF signalling is sufficient to mediate the PEC activation and formation of cellular crescents, the hallmark of RPGN. In this comment, we make an attempt to assemble the pieces of the puzzle arguing that the activated PECs might play a significant role and could represent a target for novel treatment strategies for RPGN and FSGS.

A properly established and maintained podocyte intercellular junction, or slit diaphragm, is a necessary component of the selective permeability barrier of the kidney glomerulus. The observation that mutation or deletion of the slit diaphragm transmembrane protein nephrin results in failure of podocyte foot process morphogenesis and concomitant proteinuria first suggested the hypothesis that nephrin serves as a component of a signaling complex that directly integrates podocyte junctional integrity with cytoskeletal dynamics. The observations made herein provide the first direct evidence to our knowledge for a phosphorylation-mediated signaling mechanism by which this integrative function is derived. Our data support the model that during podocyte intercellular junction formation, engagement of the nephrin ectodomain induces transient Fyn catalytic activity that results in nephrin phosphorylation on specific nephrin cytoplasmic domain tyrosine residues. We found that this nephrin phosphorylation event resulted in recruitment of the SH2–SH3 domain–containing adapter protein Nck and assembly of actin filaments in an Nck-dependent fashion. Considered in the context of the role of nephrin family proteins in other organisms and the integral relationship of actin dynamics and junction formation, these observations establish a function for nephrin in regulating actin cytoskeletal dynamics.