title: Inhibition of the VEGF signalling pathway and glomerular disorders.
abstract: Anti-cancer therapeutic approaches targeting the vascular endothelial growth factor (VEGF) ligand (anti-VEGF) or inhibiting its receptors (RTKI) have recently been developed. In spite of the promising results achieved, a serious drawback and dose-limiting side effect is the development, among others, of renal complications. This encompasses two glomerular pathological entities, namely minimal change/focal segmental glomerulosclerosis and thrombotic micro-angiopathy, involving two distinct cell types, podocytes and endothelial cells, respectively. The mechanisms that link anti-cancer therapy by RTKI to podocyte dysfunction and nephrotic level proteinuria are still poorly understood. Nevertheless, recent findings strongly suggest a central role of RelA, the master subunit of NF-κB and c-mip, an active player in podocyte disorders. RelA, which is up-regulated following anti-VEGF therapy, is inactivated by RTKI, leading to c-mip over-expression in the podocyte. This results in severe alterations in the architecture of podocyte actin cytoskeleton and subsequent severe proteinuria. Hence, clarifying the mechanisms linking c-mip and RelA as key pathogenic factors represents a critical goal in the understanding of different glomerulopathies. In the context of VEGF-targeted anti-cancer therapy, the study of these mechanisms along with the molecular cross-talk between podocyte and endothelial cell constitutes the basis for the emerging field of onconephrology.
authors.affiliation: INSERM, U955, Equipe 21, Créteil, France Université Paris-Est Créteil Val-de-Marne, Créteil, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Ollero
authors.affiliation: INSERM, U955, Equipe 21, Créteil, France Université Paris-Est Créteil Val-de-Marne, Créteil, France AP-HP, Groupe Hospitalier Henri Mondor-Albert Chenevier, Service de Néphrologie, Créteil, France.
authors.forename: Djillali
authors.initials: D
authors.lastname: Sahali
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy*; D006801:Humans; D050199:Podocytes; D015398:Signal Transduction / Q000187:drug effects*; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D042442:Vascular Endothelial Growth Factors
keywords: NF-κB; c-mip; nephrotic syndrome; podocyte; receptor tyrosin kinase