Abstract
The impairment of mesangial cell function was recently found in renal glomeruli isolated from streptozocin-induced diabetic rats. Since mesangial cells possess the polyol pathway, the accumulation of sorbitol in the diabetic state has been suggested to be causally related to mesangial cell dysfunction. However, the precise mechanism of mesangial cell dysfunction has not been clarified. In order to further elucidate the metabolic abnormalities of these cells induced by high concentrations of glucose, myo-inositol metabolism was evaluated in cultured rat mesangial cells.
By exposing the cells to a high concentration of glucose (55mM), the intracellular myo-inositol content was significantly decreased from 11.0±1.0 to 2.8±0.5 nmol/mg protein, and the sorbitol content was increased 12-fold. These changes were revealed in a dose-dependent manner, and reversed by aldose reductase inhibitor. In order to examine the mechanism of myo-inositol depletion, the uptake of myo-inositol by mesangial cells was studied. Most myo-inositol uptake was Na-dependent and saturable. Glucose inhibited myo-inositol uptake in a dose-dependent manner and kinetic analysis using Lineweaver-Burk and Dixon plots revealed that the inhibition was competitive. The addition of aldose reductase inhibitor was not able to prevent the inhibition of myo-inositol uptake. In conclusion, under the excess of ambient glucose, intracellular myo-inositol content was decreased partly via the reduction of myo-inositol uptake produced by glucose. These metabolic derangements might be responsible for the impairment of mesangial cell function.
