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

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".