OXIDATION OF LOW-DENSITY-LIPOPROTEIN BY MESANGIAL CELLS MAY PROMOTE GLOMERULAR INJURY

Low density lipoprotein (LDL) deposition and local oxidation play a ke y role in the pathogenesis of atherosclerosis and may likewise contrib ute to glomerular injury. These studies were designed to determine whe ther cultured human mesangial cells oxidize homologous LDL and to comp are the effects of unmodified and oxidized lipoprotein on cell prolife ration, viability and eicosanoid production. Cell-mediated lipoprotein oxidation was demonstrated and could be suppressed by oxygen free rad ical scavengers and inhibitors of arachidonic acid metabolism. When in cubated with cells, oxidized LDL (Ox-LDL) at concentrations up to and including 100 mu g/ml reduced H-3-thymidine incorporation without caus ing cytotoxicity as assessed by lactate dehydrogenase release. Under t he same conditions there was a concentration-dependent increase in the synthesis of prostaglandins E(2), 6-keto-PGF(1 alpha) and thromboxane B-2. In contrast, unmodified LDL enhanced DNA synthesis at concentrat ions less than 40 mu g/ml and had little effect on eicosanoid producti on. These results demonstrate that exogenous oxidized LDL inhibits mes angial cell proliferation and increases eicosanoid synthesis. Unmodifi ed lipoprotein can be directly oxidized by these cells through mechani sms that involve generation of oxygen free radicals.