Cellular Mechanisms of Lipid Injury in the Glomerulus

Hyperlipidemias may play a role in the progression of various renal diseases, including diabetes mellitus. We therefore examined the characteristics of low-density lipoprotein (LDL) binding and uptake in cultured rat mesangial cells. Mesangial cells bound and took up LDL in a manner consistent with specific receptor mediation. Furthermore, exposure of mesangial cells to LDL enhanced intracellular cholesteryl esterification and decreased de novo cholesterol synthesis. Mesangial cells expressed mRNA for LDL receptor and their expression was downregulated after preloading of cells with LDL. These results are consistent with regulation of cholesterol uptake and metabolism by a specific LDL receptor mechanism. During diabetes the apolipoprotein B of LDL undergoes nonenzymatic glycation, which may alter its affinity for the LDL receptor. Glycation of LDL reduced its affinity for binding to the receptor sites and decreased its uptake by mesangial cells. Thus, during diabetes less LDL may be taken up and more remain extracellularly, where it can be trapped in the matrix. Oxidation of LDL bound to extracellular matrix is believed to be a major factor in the pathobiology of hyperlipidemias. Specific scavenger receptors for oxidized LDL have been described and cloned. We therefore examined whether rat mesangial cells bound and took up oxidized LDL. We demonstrated low-affinity but high-capacity binding sites for oxidized LDL on mesangial cells. In contrast to LDL, which supported mesangial cell proliferation, oxidized LDL was cytotoxic for the cells and resulted in stimulation of mesangial cell prostaglandin E2 production. Trapping of LDL in the extracellular matrix is considered an initial event in LDL-induced vascular pathology. We therefore evaluated binding of LDL and modified LDL to extracellular matrix produced by cultured mesangial cells. Mesangial matrix had a high capacity to bind LDL and modified LDL (glycated or oxidized) in a nonsaturable manner. These results obtained with cultured mesangial cells and their matrix allow the formulation of a working hypothesis. Under normal eulipemic conditions mesangial cells handle LDL in a regulated manner. During hyperlipidemia or expansion of extracellular matrix LDL accumulates in the matrix. There LDL would be subject to oxidative modifications, especially under conditions of mesangial cell stress, such as inflammatory, mechanical, or ischemic injury. Part of the oxidized LDL could be taken up by scavenger receptors on mesangial cells and monocyte-macrophages, resulting in foam cell formation. Excess oxidized LDL, and specifically the lipid peroxides and lysolipids of oxidized LDL, would act as cytotoxic agents on mesangial, epithelial, and endothelial cells, thereby contributing to a vicious cycle of cell damage and sclerosis.