VEGF and the diabetic kidney: More than too much of a good thing

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Abstract

Over a decade and a half has passed since the publication of early reports hinting at a pathogenetic role for vascular endothelial growth factor (“VEGF”) in the development of diabetic kidney disease. In diabetic rats, renal mRNA levels of the VEGF-A isoform were upregulated and administration of a VEGF-A neutralizing antibody attenuated albuminuria: VEGF was “bad” in diabetic nephropathy. Since that time, our understanding of the complexity of the renal VEGF system has advanced. Unlike its experimental counterpart, human diabetic nephropathy is associated with diminished VEGF-A levels and experience in the oncological setting has taught us that VEGF blocking therapy can cause adverse renal effects in patients. Correspondingly, investigational studies in cultured cells and rodent models have demonstrated that the biological effects of the VEGF system are dependent not only on the amount of VEGF, but also the type of VEGF, its sites of action and the prevailing milieu. Here we reflect back on the discoveries that have been made since those initial reports that shone the spotlight on the importance of the VEGF system in the diabetic kidney and we consider that the role of VEGF in diabetic nephropathy extends well beyond being “too much of a good thing”.

Introduction

At the turn of this millennium, the role of vascular endothelial growth factor (VEGF) in the diabetic kidney seemed like it was going to be straightforward. VEGF was “up” in diabetic rats and blockade of its actions attenuated albuminuria: VEGF was “bad” in diabetic nephropathy. Since that time, our understanding of the complex paracrine signaling cascades that are mediated by the VEGF family has expanded. It has become apparent that it is not simply the amount of “VEGF” that is important, but also the type of VEGF, the sites of VEGF action and the context in which VEGF-mediated signaling occurs. These advances have provided a gold-standard framework against which our knowledge of the actions of other regulators of cellular function in the diabetic kidney can be compared. Here, review the evolution of the community's understanding of the role of VEGF in the diabetic kidney and how we came to recognize that this role is not simply the case of being “too much of a good thing”.

Section snippets

The VEGF System

VEGF belongs to the VEGF/platelet-derived growth factor (PDGF) super-gene family, whose gene products are homodimers that share eight conserved cysteine residues. In humans, there are five secreted glycoproteins that make up the VEGF family member: VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF). VEGF-E is encoded by certain viruses and its gene is not contained within the human genome. The most extensively studied of these family members is VEGF-A and if a person is referring

The Renal VEGF System

In the kidney, VEGF-A is expressed predominantly by glomerular podocytes. However, these are not the sole cells that express the glycoprotein, with VEGF-A mRNA also detectable in distal tubules and in collecting ducts (Cooper et al., 1999). VEGFR-2, in contrast, is expressed by glomerular endothelial cells and by the endothelial cells of the peritubular capillaries, as well as by cortical and renomedullary interstitial fibroblasts (Cooper et al., 1999). Thus, canonical VEGF signaling within the

Early Studies on the Role of VEGF-A/VEGFR-2 Signaling in Experimental Diabetic Nephropathy

One of the earliest and most influential studies describing the expression patterns of VEGF-A and VEGFR-2 in the diabetic kidney was published by Cooper and co-workers in 1999 (Cooper et al., 1999). In that study, the investigators observed that glomerular VEGF-A mRNA levels were increased as early as three weeks after the induction of diabetes with streptozotocin (STZ) in rats and that this upregulation persisted at least until eight months after diabetes induction (Cooper et al., 1999).

VEGF-A Expression Is Downregulated in Human Diabetic Kidney Disease and Blockade of its Actions Induces Kidney Injury

Whereas VEGF-A expression is often reported as being upregulated in the kidneys of rodents with diabetes, the opposite pattern has been observed in human kidney disease. This discordance is almost certainly the consequence of differences in the renal phenotype of the two species, i.e. unlike humans with diabetic nephropathy, diabetic rodents almost never develop significant glomerulosclerosis and end-stage renal disease. For instance, in 2004 Baelde and co-workers reported that the expression

The Actions of VEGF-A/VEGFR-2 Signaling Are Influenced by the Local Milieu

Comparison of the apparently beneficial renal effects of anti-VEGF therapies in rodents with early diabetes and the apparently detrimental renal effects of anti-VEGF therapies in humans, serves to illustrate that the biological effects of the VEGF system are influenced by the prevailing hemodynamic and metabolic milieu. As an example, in 2007 our own group published our finding that treatment of transgenic hypertensive (mRen-2)27 rats with the VEGFR-2 tyrosine kinase inhibitor vandetanib caused

The Effects of VEGF in Diabetic Nephropathy Are Dosage Sensitive

By and large, the studies reviewed thus far have tended to rely on therapeutic maneuvers that alter the relative activity of the VEGF-A/VEGFR-2 system. In doing so, these studies have pointed to a reno-protective effect of VEGF antagonist therapy in most rodents with experimental diabetes (de Vriese et al., 2001, Sung et al., 2006, Yuen et al., 2012) that contrasts with the detrimental renal effects that may occur in patients receiving anti-VEGF treatment for cancer (Eremina et al., 2008) and

The “Type’ of VEGF Influences the Development of Kidney Disease in Diabetes

Not only does the amount of VEGF-A appear to be critical to the maintenance of normal glomerular homeostasis, but so too does the type of VEGF-A. In this respect, evidence has begun to emerge pointing to a possible role that VEGFxxxb isoforms may play in diabetic nephropathy. As discussed earlier, the in vivo effects of the VEGFxxxb isoforms in the kidney are relatively understudied and, to some extent at least, controversial (Bates et al., 2013, Harris et al., 2012). Unlike the phenotype of

The Actions of the Renal VEGF System Are Not Limited to the Renal Glomerulus

The focus of most studies of the actions of the VEGF system in the diabetic kidney has tended to be on its glomerular effects and, as a consequence, these studies have significantly advanced our understanding of how paracrine signaling networks regulate glomerular cell function (Siddiqi & Advani, 2013). However, as reported in the early publication by Cooper et al., the glomerulus is not the only site of VEGF-A expression in the kidney (Cooper et al., 1999). It is also present within the

Summary

In summary, the balance of evidence appears to suggest that therapeutic strategies that block canonical VEGF-A/VEGFR-2 signaling are unlikely to find a clinical niche for the treatment of diabetic kidney disease in patients. Nonetheless, the insights that have been gleaned from the study of the renal VEGF system in diabetes over the past decade and a half have profoundly advanced our understanding of the regulation, impact and intricacy of paracrine signaling networks. The actions of the renal

Acknowledgements

SM is a Canadian Diabetes Association Post-Doctoral Fellow. The Advani Lab is supported by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Diabetes Association and Kidney Foundation of Canada. We apologize to the authors of the many excellent studies and journal articles that we have not been able to cite because of space constraints.

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    Conflicts of Interest: The authors declare that there are no conflicts of interest regarding the publication of this paper.

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