Interactions of low density lipoprotein with rat mesangial cells

Abstract

Hyperlipidemia may contribute to the pathogenesis of glomerular sclerosis. We therefore studied binding and uptake of low density lipoprotein (LDL) by cultured rat mesangial cells. In addition effects of LDL on PGE2 synthesis and cell proliferation were determined. At 4 degrees C mesangial cells bound [125I] LDL in a time- and concentration-dependent manner with half-maximal binding observed at 5 micrograms/ml of LDL protein. Binding was blocked by excess unlabeled LDL and by heparin. Uptake (binding plus internalization) of LDL at 37 degrees C markedly exceeded binding at 4 degrees C, continued to increase even with longer periods of incubation, and showed no saturability, consistent with uptake of LDL by mesangial cells. Further evidence for LDL uptake by mesangial cells was obtained by use of the fluorescent probe 1,1'-dioactadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate-labeled LDL (Dil-LDL). Incubation of mesangial cells with Dil-LDL at 37 degrees C showed positive fluorescence for all mesangial cells, indicating uptake of the Dil-LDL. LDL had a biphasic effect on mesangial cell proliferation as determined by [3H] thymidine incorporation. LDL at 10 micrograms/ml enhanced [3H] thymidine uptake modestly, but significantly, whereas a progressive and marked inhibition occurred at LDL concentration from 100 to 500 micrograms/ml. While LDL at 10 and 100 micrograms/ml significantly stimulated PGE2 production, inhibition of PGE2 by meclofenamate did not influence the effects of LDL on [3H] thymidine incorporation. We conclude that mesangial cells show specific binding and uptake of LDL and that high concentrations of LDL markedly decrease mesangial cell proliferation. These findings may pertain to the pathogenesis of glomerular lesions in hyperlipidemia of renal disease.

Probucol Suppresses Initiation of Chronic Hemodialysis Therapy and Renal Dysfunction-Related Death in Diabetic Nephropathy Patients: Sakura Study

“…Table 3 shows that probucol decreased total cholesterol and LDL-cholesterol. Lipids play an important role in the pathogenesis of glomerular sclerosis 35,36) , and LDL was taken up by mesangial cells 37,38) . Thus, the LDL-cholesterol-lowering action of probucol may also contribute to the beneficial effects of probucol on diabetic nephropathy.…”

Renal Accumulation of Biglycan and Lipid Retention Accelerates Diabetic Nephropathy

“…5 Mesangial and glomerular epithelial cells express low-density lipoprotein (LDL) receptors and are capable of endocytosis of bound LDL. 6,7 We and others have demonstrated that hyperlipidemia and diabetes cause accumulation of renal foam cells in animal models, 8 -10 and we recently demonstrated that lowering of lipid levels via dietary means limits progression of renal injury. 10 Increased renal deposition of apolipoproteins (apo) B and/or E is associated with increased mesangial cellularity, increased proteinuria, and increased severity of glomerulosclerosis in a variety of glomerular diseases in humans.…”

Cholesterol-lowering therapy may retard the progression of diabetic nephropathy

“…The mechanism by which hypercholesterolaemia causes or aggravates glomerular injury is not known. Specific binding and uptake of LDL has been demonstrated in rat mesangial cells [18]. In human nephritic kidneys, glomerular epithelial and mesangial cells have been shown to express both LDL receptors and scavenger receptors [19].…”