VEGF signaling and production has been assessed in cultured mesangial cells, in response to high glucose concentrations. The high glucose concentration resulted in increased VEGF mRNA and protein expression. This increase was prevented by inhibition of PKC (46,47). Other investigators have demonstrated VEGF production in glomerular endothelial cells, proximal and distal tubular cells as well as confirming the mesangial cell findings (25,48,49). High ambient glucose concentrations have also been shown to stimulate production of VEGF in mouse podocytes (50). Exogenous VEGF stimulated the production of a3 (IV) collagen by immortalized mouse podocytes (51). SU5416, a pan-VEGF receptor inhibitor prevented the increase in VEGF-stimulated collagen production and collagen production secondary to TGF-Pj seen in this model (51). However, VEGF had no effect on a5 (IV) collagen. These results suggest that podocyte-derived VEGF may play an important role in collagen production in diabetic glomerulopathy and that TGF-Pj induced matrix accumulation may work partly through this mechanism. In a subsequent study by the same group, pilot results suggest that the stimulatory effect of TGF-Pj on a3 (IV) collagen is partly dependent on the podocyte's endogenous VEGF system, operating in an autocrine loop, possibly involving the receptor, VEGFR-1 and signaling through the PI3 kinase and PKC pathways (52). AGE products and angiotensin II, stimuli highly relevant to the diabetic milieu, have also been reported to induce VEGF secretion in cultured human mesangial cells (25,49,53). Moreover, VEGF stimulation of endothelial cells caused an increase in nuclear factor-KB and an increase in ACE further extending the relationship, probably a two way interaction, between VEGF and the renin-angiotensin system (54,55).
Was this article helpful?