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

Low density lipoprotein (LDL) deposition and local oxidation play a key role in the pathogenesis of atherosclerosis and may likewise contribute to glomerular injury. These studies were designed to determine whether cultured human mesangial cells oxidize homologous LDL and to compare the effects of unmodified and oxidized lipoprotein on cell proliferation, viability and eicosanoid production. Cell-mediated lipoprotein oxidation was demonstrated and could be suppressed by oxygen free radical scavengers and inhibitors of arachidonic acid metabolism. When incubated with cells, oxidized LDL (Ox-LDL) at concentrations up to and including 100 mu g/ml reduced H-3-thymidine incorporation without causing cytotoxicity as assessed by lactate dehydrogenase release. Under the 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 concentrations less than 40 mu g/ml and had little effect on eicosanoid production. These results demonstrate that exogenous oxidized LDL inhibits mesangial cell proliferation and increases eicosanoid synthesis. Unmodified lipoprotein can be directly oxidized by these cells through mechanisms that involve generation of oxygen free radicals.