The vascular endothelial growth factor (VEGF) system is the preeminent example of an intraglomerular signalling network, being essential for renal development and adult glomerular homeostasis and being inextricably implicated in the pathogenesis of a range of renal diseases. Although over a decade has passed since the glomerular VEGF-A isoform was first recognized for its essential role in renal development and disease [1,2], it is more recently that the actions of the VEGF system have been appreciated as extending far beyond those arising from a simple ligand–receptor interaction. Sophisticated genetic manipulation strategies and other technological advances have now firmly positioned the VEGF system as the exemplar of the multifarious manner in which components of the renal glomerulus may communicate with each other and with themselves. This mini-review spotlights recent advances in our understanding of the renal VEGF system, focusing on how the biologic effects of this system are mediated by autocrine/paracrine actions, novel receptor-mediated responses, isoform-specific effects and the prevailing metabolic milieu.
THE VASCULAR ENDOTHELIAL GROWTH FACTOR SYSTEM
In humans, the VEGF family consists of five secreted homodimeric glycoproteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor. When referring to ‘VEGF’, an individual is usually making reference to the VEGF-A isoform, which is widely recognized for its essential role in the regulation of endothelial cell survival, proliferation, differentiation and migration as well as endothelium-dependent vasodilatation and vascular permeability. The importance of VEGF-A in (patho)physiological angiogenesis is illustrated by the observations that deletion of the isoform is embryonic lethal  and augmentation of the cytokine is critical to tumour vessel growth .
VEGF-A is encoded by a gene that consists of eight exons that, through alternative splicing, give rise to at least six different isoforms distinguished by their amino acid length, in humans designated: VEGF121, VEGF145, VEGF165, VEGF183, VEGF189 and VEGF206. The most abundant isoform is VEGF165, which is one amino acid shorter in rodents (VEGF164). VEGF-A exerts its biologic effects by binding to its transmembrane receptors: VEGFR-1 [previously known as fms-like tyrosine kinase-1 (Flt-1)] and VEGFR-2 [formerly murine foetal liver kinase 1 (flk-1)/human kinase insert domain receptor (KDR)] and coreceptors neuropilin-1 and neuropilin-2.
The majority of the actions of VEGF-A are induced through its interaction with VEGFR-2, which is both necessary and sufficient to mediate the normal biological response under most circumstances [5,6]. In comparison to VEGFR-2, the tyrosine kinase activity of VEGFR-1 is weak and the role of VEGFR-1 is consequently less well defined, the receptor functioning, at least in part, in a ‘decoy’ capacity. In addition to the full-length membrane-bound receptor, however, the VEGFR-1 gene also gives rise to a second splice variant, which is a soluble, secreted truncated receptor, termed sFLT1 . The significance of sFLT1 as an endogenous VEGF-A antagonist and pathogenetic mediator in the development of preeclampsia has been appreciated for some time . Very recently however, and as reviewed below, it has been discovered that the same secreted protein also has essential autocrine actions in glomerular podocytes [9▪▪]. Finally, adding a further layer of complexity to the VEGF system is the existence of antiangiogenic isoforms that are identical in length to their proangiogenic counterparts, distinguishable by their terminal amino acid sequence . These alternative isoforms are given the nomenclature VEGFxxxb, the xxx indicating the amino acid length and, being unable to induce the efficient auto-phosphorylation of VEGFR-2, the isoforms appear to function by competitively antagonizing VEGF-A/VEGFR-2 signalling .
GLOMERULAR VASCULAR ENDOTHELIAL GROWTH FACTOR-A ACTIONS
Unlike in many other tissue beds, constitutive glomerular VEGF-A expression persists into adulthood . The principal source of VEGF-A in the renal glomerulus is the podocyte, which expresses the VEGF121, VEGF165 and VEGF189 isoforms, VEGF165 being the most abundant . A series of studies over the past decade have demonstrated that manipulation of podocyte VEGF-A gene dosage results in profound effects on the glomerular phenotype. During development, VEGF-A obliteration prevents glomerular filtration barrier formation and results in perinatal lethality; podocyte VEGF-A heterozygosity causes endotheliosis and proteinuria reminiscent of preeclampsia; and VEGF-A overexpression results in a collapsing glomerulopathy . In the adult kidney, inducible podocyte VEGF-A deletion results in proteinuria and a thrombotic microangiopathy-type picture, akin to the renal injury that may be observed in some patients receiving anti-VEGF agents in the oncology setting . The effects of VEGF-A overexpression in the kidneys of adult or weaned mice are more variable however, with significant proteinuria described in some studies [15,16], but not in others [17▪,18].
AUTOCRINE ACTIONS OF THE VASCULAR ENDOTHELIAL GROWTH FACTOR-A/VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2 SYSTEM IN PODOCYTES
Whereas the podocyte is the predominant source of VEGF-A within the renal glomerulus, the predominant site of VEGFR-2 expression is the glomerular endothelium . This suggests that the signalling cascade mediates paracrine communication acting in the opposite direction to the primary filtrate. Although the mechanisms that facilitate this directional communication remain incompletely understood, recent evidence points to a pivotal role of WT-1 dependent sulphatases in facilitating VEGF-A bioavailability through modulation of the composition of the glomerular extracellular matrix . The significance of VEGF-A in the normal development of the glomerular endothelium and in the formation of endothelial fenestrations is undisputed [1,15,20]. In contrast, however, the presence and actions of VEGFR-2 in podocytes are unclear. One study was unable to detect VEGFR-2 in podocytes in vivo, or in podocytes isolated from mouse kidneys, and was unable to discern a glomerular phenotype with podocyte-specific VEGFR-2 deletion . In contrast, a number of other groups have reported the presence of VEGFR-2 on podocytes in vivo, using immunogold electron microscopy, immunofluorescence or coimmunoprecipitation [16,21,22▪,23]. It has been speculated that this apparent discordance could have arisen if there was incomplete Cre-mediated VEGFR-2 excision in the former study [24▪]. Regardless, the presence of functionally active VEGFR-2 in cultured immortalized podocytes of human and murine origin is generally accepted . Assuming the presence of functionally active VEGFR-2 in podocytes, what then is the biological significance of the transmembrane receptor in these specialized visceral epithelial cells? Recent advances have suggested that podocyte VEGFR-2 plays a significant role in both autocrine regulation of podocyte function and in the prevention of development of diabetic albuminuria [22▪,26].
Given the abundance of podocyte VEGF-A, the presence of both ligand and receptor in the same cell implies the existence of an autocrine loop. In this regard, experiments have revealed an intriguing interaction between VEGFR-2 and the slit-pore protein nephrin in conditionally immortalized mouse podocytes . Podocyte-expressed nephrin plays a fundamental role in preserving filtration barrier integrity, as illustrated by the heavy proteinuria that may occur in individuals affected by the condition congenital nephrotic syndrome of the Finnish subtype, arising as a consequence of a heritable mutation in the nephrin-encoding gene, NPHS1. Through a combination of studies employing mass spectrometry, immunoprecipitation, GST-binding and blot overlay, investigators recently demonstrated an interaction between the cytoplasmic domains of VEGFR-2 and nephrin in podocytes . In the model derived from these and subsequent experiments, the authors propose that VEGFR-2–nephrin interaction (under regulatory control of tyrosine phosphorylation of both proteins) forms a multiprotein complex with the adapter protein, Nck, providing a link to the actin cytoskeleton. This model provides a conceptual framework by which VEGF-A/VEGFR-2 binding may induce changes in podocyte cell shape, offering a plausible mechanism for podocyte foot process effacement and proteinuria occurring as a result of VEGF-A overexpression [16,28].
An alternative manner in which VEGF-A autocrine signalling in podocytes may be of (patho)biological significance is through the emerging paradigm of VEGF-A resistance. In diabetes, exposure of tissue beds such as those of the retina, peripheral nervous system and renal glomerulus to high glucose concentrations over a prolonged period of time can cause the development of organ-specific complications. In a landmark study of diabetic retinopathy, published in 2009, investigators unearthed a novel mechanism for hyperglycemia-induced retinal injury whereby activation of the protein kinase C δ (PKCδ) isoform promotes pericyte apoptosis. In that study, investigators observed that PKCδ induced activation of the protein tyrosine phosphatase Src homology-2 domain-containing phosphatase-1 (SHP-1) and the subsequent dephosphorylation of platelet-derived growth factor-ß (PDGF-ß) , one of several tyrosine kinase receptors known to be downregulated by the phosphatase [22▪]. In follow up to this work, the same group sought to explore whether a similar signalling cascade was at play in glomerular podocytes, focusing this time on the role of PKCδ/SHP-1 in the regulation of glomerular VEGF-A resistance [22▪]. The authors reported that in cultured podocytes and cultured glomerular endothelial cells, high glucose concentrations similarly activated PKCδ resulting in the downstream activation of p38 mitogen-activated protein kinase (p38 MAPK) and SHP-1, which antagonized VEGFR-2 signalling and resulted in podocyte apoptosis [22▪]. Consistent with their observations in cultured cells, and further evidence for a critical role of PKCδ in mediating diabetes-induced glomerular injury, the authors went on to describe a reduction in extracellular matrix accumulation and albuminuria in diabetic mice genetically deficient in PKCδ [22▪].
AUTOCRINE SIGNALLING BY SOLUBLE FMS-LIKE TYROSINE KINASE-1 IN PODOCYTES
Although the studies described above support an autocrine function for VEGF-A in glomerular podocytes, a groundbreaking study [9▪▪] recently revealed that the principal member of the VEGF system that plays an autocrine role in podocytes is sFLT1. In comparison to the full-length transmembrane protein, sFLT1 is the predominant VEGF receptor present on podocytes, the gene encoding a protein consisting of six immunoglobuin repeats and a unique C-terminus that enables ligand binding but does not have the capacity to span the cell membrane or mediate tyrosine phosphorylation-dependent signalling. In an elegant and exhaustive series of experiments, investigators built upon an initial observation that podocyte-specific Flt1 deletion resulted in disruption of the podocyte cytoskeletal architecture and the development of heavy proteinuria [9▪▪]. Intriguingly, this phenotype was not observed in mutant mice lacking the tyrosine kinase domain of the protein indicating that FLT1-dependent tyrosine phosphorylation is dispensable to podocyte viability. Rather, the authors found that binding of sFLT1 to podocytes was capable of inducing rapid actin reorganization and cell adhesion demonstrating that it is the soluble, kinase-deficient isoform of FLT1 that is essential to the maintenance of podocyte integrity. The combination of subsequent bioinformatic-based studies and further work revealed that sFLT1 exerts its effects through binding to the glycosphingolipid GM3 highly enriched in membrane lipid rafts, the resulting complex itself associating with the transmembrane heparin sulphate proteoglycans syndecan 1 and 4 and the slit-pore protein nephrin. These novel interactions provide a plausible mechanism through which sFLT1 may regulate autocrine signalling and cytoskeletal rearrangements in podocytes [9▪▪]. Thus, a hitherto unrecognized, yet biologically essential role for a member of the VEGF system, sFLT1, has now been identified, expanding the repertoire of actions of this protein beyond those of a decoy receptor.
ANTI-ANGIOGENIC VASCULAR ENDOTHELIAL GROWTH FACTOR-A ISOFORMS
Given that the actions of the VEGF system are far more intricate than perhaps initially appreciated, it is unsurprising that the regulation of the pathway is similarly intricate, being equally influenced by the presence of endogenous regulators germane to the VEGF system and by the broader actions of the metabolic or haemodynamic microenvironment. In the case of the endogenous regulation of the VEGF system, much work is still needed to define the precise biologic actions of the VEGFxxxb family members within the renal glomerulus and to investigate the effects of therapeutic manipulation of these isoforms. VEGFxxxb family members are expressed in apparently equal abundance to their more widely appreciated pro-angiogenic counterparts , wherein proximal splice site selection gives rise to the classical VEGFxxx isoforms and distal splice site selection results in the VEGFxxxb isoforms [17▪]. Although they are regarded as inhibitors of angiogenesis , the biologic effects of VEGF165b isoforms are not necessarily diametrically opposed to those mediated by the conventional isoforms. For instance, whereas VEGF164 deletion causes proteinuria, overexpression of VEGF165b in podocytes yields a milder phenotype characterized by a reduction in glomerular ultrafiltration fraction . In a follow-up to these initial observations, investigators recently sought to determine whether overexpression of the VEGF165b isoform could rescue the phenotype in adult mice simultaneously overexpressing VEGF164. In contrast to some earlier studies [15,16], but consistent with others [17▪,18], the authors did not observe an increase in abuminuria in VEGF164 overexpressing mice, although they did identify that the mice exhibited an early increase in ultrafiltration coefficient that was prevented by simultaneous VEGF165b overexpression [17▪,18].
VASCULAR ENDOTHELIAL GROWTH FACTOR-A AND DIABETIC NEPHROPATHY
The significance of extrinsic influencers on the biologic effects of the VEGF system is best exemplified through the study of the actions of the signalling pathway in renal disease. Most extensively investigated has been the role of the VEGF system in the pathogenesis of diabetic nephropathy, the most common cause of end-stage renal disease worldwide. Several studies have described an upregulation of VEGF-A in experimental diabetes [2,33] and described an antialbuminuric effect of VEGF antagonism employing a variety of pharmacological or genetic approaches [21,34,35]. In contrast, the expression patterns of VEGF-A in human diabetic nephropathy appear to be more variable, the cytokine being either upregulated or downregulated according to the stage of disease [36–40]. The discordance between a plausibly pathogenetic effect of VEGF-A in the diabetic glomerulus and a generally reno-protective function under nondiabetic conditions has been termed the VEGF paradox [41▪] and has been the subject of investigation of four recent studies.
In one recent study [42▪], we explored the biologic effects of VEGFR-2 tyrosine kinase inhibition with a small molecule antagonist in diabetic mice. In these experiments, we noted a reduction in albuminuria and in hyperfiltration with VEGFR-2 inhibition in diabetic mice, despite a class-effect rise in blood pressure and urine albumin excretion in nondiabetic animals [42▪]. Mechanistically, the antialbuminuric effects of VEGFR-2 blockade were eliminated in diabetic mice genetically deficient in endothelial nitric oxide synthase (eNOS), implicating this enzyme as a key downstream regulator of the albuminuric actions of VEGFR-2 in diabetes [42▪]. Highlighting the dose effect of extrinsic influencers, we separately observed that the deleterious effects of VEGFR-2 blockade, which occurred in hypertensive transgenic (mRen-2)27 rats , were negated in the presence of concomitant diabetes accompanied by an increase in eNOS–nitric oxide activity . Consistent with a pathophysiological effect of VEGF-A in diabetic nephropathy, a separate study  described the development of nodular glomerulosclerosis arising as a consequence of VEGF-A overexpression in diabetic mice. In contrast, a further study [46▪] reported an acceleration of renal injury with the combination of streptozotocin-induced diabetes and genetic podocyte VEGF-A deletion. Together, these studies highlight that even within a ‘single’ disease type, the functions of VEGF-A or the effects of VEGF inhibition may be variable, being profoundly influenced by subtle alterations in the metabolic milieu and the method and magnitude of VEGF-A/VEGFR-2 change.
The VEGF system plays a fundamental role in renal development, in the adult kidney and in disease. Whereas recent studies have continued to demonstrate the importance of VEGF family members in the pathogenesis of a range of kidney diseases and as targets for novel therapeutics development [47–50], major advances have been made in elucidating the intricacies of this intraglomerular signalling network. The glomerular VEGF system is an exemplar of autocrine/paracrine communication within a tissue bed, itself regulated by influencers that are both intrinsic and extrinsic to the system (Fig. 1). The interactions of the VEGF system may be intricate, but to quote Aristotle ‘In all things of nature there is something of the marvellous’.
Dr Advani is supported by a Clinician Scientist Award from the Canadian Diabetes Association and this work was supported, in part, by grants from the Canadian Diabetes Association and from the Canadian Institutes of Health Research.
Conflicts of interest
There are no conflicts of interest.
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