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Podocytes are critically important for maintaining integrity of the glomerular filtration barrier and preventing albuminuria. Recently it has become clear that to achieve this they need to be insulin sensitive, and produce an optimal amount of vascular endothelial growth factor-A (VEGF-A). In other tissues insulin has been shown to regulate VEGF-A release but this has not been previously examined in the podocyte. Using an in-vitro and in-vivo approach we now show that insulin regulates VEGF-A in the podocyte in both mouse and man via the insulin receptor (IR). Insulin directly increases VEGF-A messenger RNA levels and protein production in conditionally immortalized wild-type human and murine podocytes. Furthermore, when podocytes are rendered insulin resistant in vitro (using stable short hairpin RNA knockdown of the IR) or in vivo (using transgenic podocyte specific IR knockout mice) podocyte VEGF-A production is impaired. Importantly, in vivo this occurs prior to the development of any podocyte damage due to podocyte insulin resistance. Modulation of VEGF-A by insulin in the podocyte may be another important factor in the development of glomerular disease associated with conditions in which insulin signaling to the podocyte is deranged.