Effects of high glucose concentrations on human mesangial cell proliferation.

Abstract

High concentrations of glucose in vitro inhibit cell proliferation and stimulate matrix protein synthesis. These studies sought to characterize the relationship between the effects of glucose on cell proliferation and matrix synthesis and to assess the mechanism(s) responsible for these cellular effects of glucose. The initial experiments showed that high glucose levels stimulate fibronectin (FN) synthesis by human mesangial cells (HMC) but only in those cultures in which cell proliferation was inhibited by glucose. To assess whether this relationship was due to an effect of glucose on the capacity of HMC to respond to cytokines, the responses of HMC to serum or cytokines were measured in the presence of different glucose concentrations. High concentrations of glucose inhibited (3H)thymidine incorporation in response to serum and platelet-derived growth factor. Under the conditions of these experiments, transforming growth factor-beta (TGF-beta) also stimulated thymidine incorporation by HMC, and high glucose concentrations inhibited thymidine incorporation in response to TGF-beta. In contrast, high concentrations of glucose did not inhibit the stimulation of FN synthesis caused by platelet-derived growth factor, serum, or TGF-beta. The antiproliferative effects of high glucose levels were first observed after 48 h of incubation and were reversible after the withdrawal of high glucose from the media. The following evidence suggest that the effects of glucose may be mediated via protein kinase C (PKC): (1) incubation with high glucose concentrations caused an increase in HMC PKC levels; (2) PKC activation with phorbol esters inhibited HMC proliferation; and (3) depletion or inhibition of PKC stimulated HMC proliferation and prevented the antiproliferative effects of glucose. In contrast to these findings, inhibitors of protein glycosylation and myo-inositol supplementation of culture media did not prevent the antiproliferative effects of glucose. In conclusion, high glucose concentrations acutely and reversibly inhibit HMC proliferation, perhaps by a PKC-dependent mechanism. Because PKC can also stimulate FN synthesis, glucose-induced changes in PKC may explain the relationship between the effects of high glucose concentrations on cell proliferation and FN synthesis.