Oxidative Modification of Low-Density Lipoprotein Enhances Mesangial Cell Protein Synthesis and Gene Expression of Extracellular Matrix Proteins

Abstract

The proliferation of intrinsic glomerular cells and the accumulation of extracellular matrix proteins are principal histopathological features seen in glomerular injury. Because of the marked similarity between the cellular and molecular events that occur in both atherosclerosis and glomerulosclerosis and the commonly accepted hypothesis that lipoproteins are implicated in the pathogenesis of glomerulosclerosis, we examined the effect of three atherogenic lipoproteins, low-density lipoprotein (LDL), oxidized (ox)-LDL, and minimally modified (mm)-LDL on the synthesis and secretion of extracellular matrix (ECM) proteins by mesangial cells. The incubation of SV-40 transformed murine mesangial cells with LDL (25–100 µg/ml) increased the synthesis and secretion of both fibronectin and laminin in a dose-dependent manner. Similarly, oxidized forms of LDL (25–100 µg/ml) increased fibronectin and laminin synthesis and secretion dose dependently. However, both oxidatively modified forms of LDL had a greater effect on increasing ECM protein synthesis than their native counterpart. Northern blot analysis showed a dose-dependent increase in mRNA transcripts for fibronectin and laminin in response to the incubation of mesangial cells with LDL, ox-LDL, and mm-LDL. Similar to the ECM protein expression data, the oxidatively modified forms of LDL had more pronounced effects on the gene expression of both fibronectin and laminin. These data show that both LDL and, perhaps more importantly, its oxidatively modified forms stimulate mesangial cells to upregulate both the gene expression and synthesis and secretion of ECM proteins, supporting a role for atherogenic lipoproteins in the pathobiology of glomerular injury.