Inhibition of the VEGF signalling pathway and glomerular disorders

Nephrol Dial Transplant. 2015 Sep;30(9):1449-55. doi: 10.1093/ndt/gfu368. Epub 2014 Dec 5.

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.

Keywords: NF-κB; c-mip; nephrotic syndrome; podocyte; receptor tyrosin kinase.

Publication types

  • Review

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Glomerulosclerosis, Focal Segmental / drug therapy*
  • Humans
  • Podocytes
  • Signal Transduction / drug effects*
  • Vascular Endothelial Growth Factors / antagonists & inhibitors*

Substances

  • Angiogenesis Inhibitors
  • Vascular Endothelial Growth Factors