Role of the VEGF-A Signaling Pathway in the Glomerulus: Evidence for Crosstalk between Components of the Glomerular Filtration Barrier

Abstract

Background/Aims: Vascular endothelial growth factor is a major regulator of angiogenesis and vascular permeability [Carmeliet et al.: Nature 1996;380:435–439]. The podocyte, the outermost layer of the glomerular filtration barrier, produces large amounts of VEGF-A. The observation that levels of VEGF-A are altered in glomerular diseases, the identification of a link between pre-eclampsia and elevated levels of a circulating soluble VEGF receptor, and the entry of anti-VEGF therapies into the clinical arena have generated intense interest in the functional role of VEGF-A in the glomerulus. Methods: A variety of studies have been performed to address the role of VEGF-A signaling in the glomerulus. These include descriptions of expression patterns in human renal biopsies, cell culture studies to dissect paracrine versus autocrine signaling roles, and manipulation of VEGF-A expression in animal models using pharmacologic, biologic or genetic approaches. Results: Exquisite dosage sensitivity to VEGF-A exists in the developing glomerulus as small reductions in the expression of VEGF-A lead to profound changes in glomerular structure and function in mice. The use of VEGF inhibitors is associated with damage to the glomerular endothelium in animal models and proteinuria in patients, suggesting that local VEGF-A production is also required for maintenance of this specialized vascular bed. Conclusions: Tight regulation of VEGF-A signaling is required for development and maintenance of the glomerular filtration barrier (GFB) and emphasizes the role of podocyte-endothelial crosstalk in the glomerulus. The relative contributions of various VEGF-A isoforms, the role of autocrine signaling in vivo and identification of factors and mechanisms that regulate constitutive expression, storage and delivery of VEGF-A in the glomerulus are still under investigation.