Receptor-mediated uptake of IDL and LDL from nephrotic patients by glomerular epithelial cells

Abstract

Although hyperlipidemia is a well-recognized complication of the nephrotic syndrome, the precise interaction of human glomerular cells and human lipoproteins, abnormal in lipid and protein composition, has not been clearly defined. This study examines receptor mediated binding, internalization and degradation as well as intracellular cholesterol metabolism of apoB-100 containing LDL and apoB,E containing IDL, isolated from patients with the nephrotic syndrome (N = 6), in human glomerular epithelial cells and skin fibroblasts. In the patients, serum LDL cholesterol level was increased threefold and IDL elevenfold as compared to healthy subjects. IDL of nephrotic patients contained 72% more cholesterol than IDL of healthy controls. No difference in lipid/protein composition was found in the LDL density range. Therefore, nephrotic and control LDL showed identical affinities for receptor mediated binding, internalization and degradation. Furthermore, inhibition of intracellular sterol synthesis and cholesteryl ester formation after incubation with LDL was comparable. In contrast, cholesterol-rich IDL of nephrotic patients was taken up by glomerular epithelial cells with higher affinity than LDL and control IDL, as well as intracellular sterol synthesis was suppressed more effectively than by control IDL. The cholesterol esterification rate of IDL from patients was enhanced 3.5-fold as compared to control IDL. In comparison to fibroblasts, glomerular epithelial cells showed about 15% of the maximal capacity for LDL uptake, but 31% for IDL from nephrotic patients. The data indicate that hypercholesterolemia of nephrotic origin cannot be explained by reduced ligand binding for LDL. ApoE containing IDL, which accumulate in nephrotic patients, were avidly taken up by glomerular epithelial cells via receptor dependent pathway. These lipoproteins could therefore play the predominant role in glomerular lipid accumulation and development of glomerulosclerosis.