MESANGIAL CELL-DNA SYNTHESIS INDUCED BY HYDROGEN-PEROXIDE, INTERLEUKIN-6, AND PLATELET-DERIVED GROWTH-FACTOR - EFFECTS OF INDOMETHACIN AND DAZMEGREL

This study indirectly examined the role of prostanoids (PG) in mediati ng rat mesangial cell (MC) DNA synthesis induced by hydrogen peroxide (H2O2), interleukin 6 (IL-6), and platelet-derived growth factor (PDGF ). MC were exposed to three daily pulses of 10(-6) mol/l H2O2 alone or in combination with IL-6 (5 ng/ml) or PDGF(10 ng/ml). In order to exa mine (indirectly) the role of PG in mediating changes in MC DNA synthe sis, indomethacin (1.5 x 10(-5) mol/l) or the thromboxane A(2) synthet ase inhibitor Dazmegrel (10(-5) mol/l) was added to the medium and DNA synthesis assessed after 72 h using H-3-thymidine incorporation (H-3- TdR). Stimulation of MC by H2O2 alone resulted in an increase in H-3-T dR of 34.7 +/- 5.5% (p < 0.01). H2O2 enhanced the mitogenic effects of IL-6 and PDGF, H-3-TdR increasing by 52 +/- 12.1% (p < 0.01) and 100 +/- 21% (p < 0.001), respectively. Indomethacin suppressed the DNA syn thesis induced by H2O2 alone, H-3-TdR decreasing by 33 +/- 12% (p < 0. 05). Indomethacin also reduced the mitogenic response to H2O2 plus IL- 6 and H2O2 plus PDGF by 91 +/- 17 and 97 +/- 12%, respectively (p < 0. 05). Dazmegrel reduced H-3-TdR when MC were exposed to H2O2 alone by 3 1.8 +/- 16% (p < 0.05) and when combined with IL-6 or PDGF by 80 +/- 2 6 and 120 +/- 13%, respectively (p < 0.05). These data suggest that th e pathways through which H2O2-induced growth of MC is mediated appear, at least in part, to involve PG, particularly thromboxane A(2).