INTERACTIONS OF HYDROGEN-PEROXIDE WITH INTERLEUKIN-6 AND PLATELET-DERIVED GROWTH-FACTOR IN DETERMINING MESANGIAL CELL-GROWTH - EFFECT OF REPEATED OXIDANT STRESS

1. This study examined the influence of H2O2, interleukin-6 and platelet-derived growth factor on the proliferation of rat mesangial cells. Mesangial cells were exposed to either a single pulse or three daily pulses of H2O2 (10(-8)-10(4) mol/l), alone or in combination with interleukin-6 (5 ng/ml) and/or platelet-derived growth factor (10 ng/ml). Proliferation was assessed after 24 h and 72 h of incubation using [H-3]thymidine incorporation and cell counts. 2. Although one pulse of H2O2 had no significant effect on mesangial cell proliferation, three daily pulses of 10(-6) mol/l H2O2 resulted in a significant increase in [H-3]thymidine incorporation of 31 (52.6, 10.3)% (median and 75th-25th interquartile range) (P<0.001). Both interleukin-6 and platelet-derived growth factor were also mitogenic to mesangial cells, [H-3]thymidine incorporation increasing by 19 (36.7, -6.7)% (P<0.05) and 53.5 (107, 21.9)% (P<0.001), respectively. The mitogenic effect of interleukin-6 was enhanced by 10(-6) mol/l H2O2 [49.9 (77.7, 12.3)%] (P<0.01), whereas the addition of 10(-6) mol/l H2O2 to platelet-derived growth factor resulted in a summated increase in [H-3]thymidine incorporation of 82.7 (113, 57.4)% (P<0.001). Incubation with all three substances simultaneously resulted in down-regulation of growth compared with H2O2 plus platelet-derived growth factor by 55.4 (77.7, 10.3)% (P<0.05). 3. These findings suggest that reactive oxygen species may play a major role in determining the mesangial cell proliferation that occurs in certain forms of glomerulonephritis, acting either alone or in combination with other growth factors.