Effect of high glucose on endothelin-1 and platelet-derived growth factor stimulation of mesangial cell protein kinase C and mitogen-activated protein kinase

grantor: University of TorontoThe purpose was to identify whether high glucose alters mesangial cell (GMC) mitogen-activated protein kinase (MAPK) activation by endothelin (ET-1) or platelet-derived growth factor (PDGF) through a diacylglycerol-sensitive protein kinase C (PKC)-dependent mechanism. We measured PKC-$\alpha,$ -$\delta$ and -$\varepsilon$ translocation and MAPK phosphorylation by immunoblot. ET-1, but not PDGF, caused translocation of PKC-$\delta$ and -$\varepsilon.$ In HG, ET-1-stimulated PKC-$\delta$ and -$\varepsilon$ translocation was increased to the particulate yet decreased to the membrane fraction. In HG, basal and ET-1-stimulated MAPK activities were enhanced. Downregulation of PKC isoforms prevented enhanced ET-1-stimulated MAPK activity. To conclude, in HG, ET-1 stimulation of PKC-$\delta$ and -$\varepsilon$ and MAPK activation is altered, which may contribute to GMC dysfunction in diabetes. This work implies that hyperglycemia interaction with vasoactive agents may contribute to mesangial cell dysfunction in diabetic nephropathy.M.Sc