Oxidative modification of low-density lipoprotein enhances the murine mesangial cell cytokines associated with monocyte migration, differentiation, and proliferation

Abstract

The oxidative modification of atherogenic lipoproteins has been proposed to induce critical interactions between the monocytes and glomerular cells that are mediated by the expression of adhesion molecules and monocyte chemoattractants. Because increased localization of atherogenic lipoproteins, including oxidatively modified low-density lipoprotein (ox-LDL) and monocytes, has been seen in experimental glomerulosclerotic lesions, we examined the ability of ox-LDL to activate mesangial cells to express macrophage-colony stimulating factor (M-CSF) and the murine homologue of human monocyte chemotactic protein-1 (JE/MCP-1) and to induce monocyte migration and proliferation. Incubation of mesangial cells with ox-LDL markedly increased M-CSF and JE/MCP-1 gene expression dose-dependently when compared with native LDL. The biologic activity of lipoprotein-induced M-CSF secretion by mesangial cells was examined by adding aliquots of native or ox-LDL-activated mesangial cell-conditioned media to bone marrow cells in a methylcellulose semisolid culture dish. Conditioned media from ox-LDL-activated mesangial cells enhanced the growth of bone marrow progenitor colonies when compared with either control or native LDL-activated cell media. The increase in progenitor colony formation in response to either LDL or ox-LDL could be attenuated by the addition of anti-M-CSF. The conditioned media obtained from lipoprotein-activated mesangial cells increased the incorporation of 3H-thymidine into monocyte DNA that could be attenuated by the addition of anti-M-CSF. Finally, the supernatant that was obtained from mesangial cells activated with ox-LDL-stimulated monocyte migration dose-dependently when compared with media that were obtained from cells incubated with native LDL. Increased monocyte migration could also be blocked by the addition of anti-JE/MCP-1. The results of these studies indicate that oxidative modification of LDL further enhances its potency to induce renal injury by stimulating M-CSF and JE/MCP-1 expression. Thus, the data suggest that ox-LDL may play a critical role similar to that of systemic vascular cells in the pathobiologic cellular events associated with glomerulosclerosis by increasing monocyte recruitment, retention, and proliferation within the mesangium.