ACTIVATION OF MESANGIAL CELLS BY THE PHOSPHATASE INHIBITOR VANADATE -POTENTIAL IMPLICATIONS FOR DIABETIC NEPHROPATHY

The metalion vanadate has insulin-like effects and has been advocated for use in humans as a therapeutic modality for diabetes mellitus. How ever, since vanadate is a tyrosine phosphatase inhibitor, it may resul t in undesirable activation of target cells. We studied the effect of vanadate on human mesangial cells, an important target in diabetic nep hropathy. Vanadate stimulated DNA synthesis and PDGF B chain gene expr ession. Vanadate also inhibited total tyrosine phosphatase activity an d stimulated tyrosine phosphorylation of a set of cellular proteins. T wo chemically and mechanistically dissimilar tyrosine kinase inhibitor s, genistein and herbimycin A, blocked DNA synthesis induced by vanada te. Vanadate also stimulated phospholipase C and protein kinase C. Dow nregulation of protein kinase C abolished vanadate-induced DNA synthes is. Thus, vanadate-induced mitogenesis is dependent on tyrosine kinase s and protein kinase C activation. The most likely mechanism for the e ffect of vanadate on these diverse processes involves the inhibition o f cellular phosphotyrosine phosphatases. These studies demonstrating t hat vanadate activates mesangial cells may have major implications for the therapeutic potential of vanadate administration in diabetes. Alt hough vanadate exerts beneficial insulin-like effects and potentiates the effect of insulin in sensitive tissue, it may result in undesirabl e activation of other target cells, such as mesangial cells.