Preferential binding of oxidized LDL to rat glomeruli in vivo and cultured mesangial cells in vitro

George Coritsidis, Vincent Rifici, Salil Gupta, Jonathan Rie, Zihe Shan, Joel Neugarten, Detlef Schlondorff

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103 Scopus citations

Abstract

Hyperlipidemia may contribute to the pathogenesis of glomerular sclerosis. We therefore compared binding and uptake of native LDL and oxidized LDL (Ox-LDL) to cultured mesangial cells (MC) and the resulting effects on prostaglandin generation and cell proliferation. Ox-LDL, prepared from native LDL by incubation with copper, was bound to MC in a concentration dependent manner with a four- to fivefold increase in binding over LDL. In competition binding experiments Ox-LDL competed to 90% with LDL for binding sites, but LDL only displaced Ox-LDL to 15%. Furthermore polyinosinic acid, which blocks binding of Ox-LDL to macrophages, inhibited binding of Ox-LDL but not that of LDL to MC. Mesangial cells also preferentially took up Ox-LDL over LDL, and Ox-LDL resulted in higher [14C] oleate incorporation into cholesteryl esters than LDL, findings consistent with different handling of Ox-LDL and LDL by MC. LDL slightly stimulated mesangial cell proliferation at low concentration (10 to 50 μg/ml of LDL) returning to control levels at 100 and 250 μg/ml. In contrast Ox-LDL inhibited cell proliferation in a concentration-dependent manner, starting at concentrations as low as 10 to 25 μg/ml of Ox-LDL. Direct observations of mesangial cells by phase contrast microscopy confirmed the cytotoxic effects of Ox-LDL. Addition of Ox-LDL to mesangial cells resulted in a concentration-dependent increase in PGE2 synthesis within one hour, while at this time point LDL had no significant effect. To assess in vivo glomerular uptake, we infused radioiodinated native LDL and Ox-LDL into the suprarenal aorta of normal Sprague-Dawley rats and determined radioactivity in isolated glomeruli. These studies showed that glomerular uptake of Ox-LDL also markedly exceeded that of LDL, reaching levels observed in the liver, a major site of LDL and Ox-LDL uptake. In conclusion, MC have binding sites for both LDL and Ox-LDL. Uptake of Ox-LDL stimulates PGE2 production and inhibits proliferation of mesangial cells, factors that may be of significance for lipid-induced glomerular injury.

Original languageEnglish (US)
Pages (from-to)858-866
Number of pages9
JournalKidney international
Volume39
Issue number5
DOIs
Publication statusPublished - May 1991

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ASJC Scopus subject areas

  • Nephrology

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