REGULATION OF INOSITOL TRANSPORT BY GLUCOSE AND PROTEIN-KINASE-C IN MESANGIAL CELLS

Since inositol (Ins) depletion appears to be an important mechanism of cell injury in diabetic glomerulopathy, we studied Ins transport in cultured rat mesangial cells during hyperglycemia. High glucose stimulated [H-3]-Ins uptake by 50 to 90% within 24 hours in a dose dependent manner. This effect was characterized by an increase in the V(max) of a Na+-dependent Ins transporter (10.3 +/- 0.2 vs. 16.4 +/- 0.4 pmol/mg/min, P < 0.005). Since high glucose also induced activation of protein kinase C (PKC) in permeabilized mesangial cells, we examined the potential role of this enzyme in the stimulation of Ins transport by glucose. Both PKC inhibition with H7 and staurosporine, and down regulation of PKC by prolonged PMA (1.6-mu-M) treatment inhibited the stimulatory effect of glucose on Ins transport. In conclusion, high glucose stimulates Na+-dependent Ins transport in mesangial cells by a mechanism mediated by PKC. This process may represent an important adaptive response of mesangial cells to hyperglycemia.