Interaction of native and oxidized lipoprotein(a) with human mesangial cells and matrix

The trapping of apolipoprotein(a) and apolipoprotein B-100 in glomeruli of patients with the nephrotic syndrome seems to be linked to a less favorable course of renal disease. To evaluate the potential role of lipoprotein(a) as a mediator of glomerular injury, we measured uptake of native lipoprotein(a) [Lp(a)] and oxidatively modified Lp(a) by cultured human mesangial cells and matrix and studied the effects of Lp(a) on mesangial cell DNA-synthesis and cellular proliferation. Uptake of Lp(a) by mesangial cells occurred at a significantly lower affinity (KD 16 micrograms/ml vs. 39 micrograms/ml) and a lower maximum degradative capacity (6.7-fold) than for LDL. Specificity of receptor mediated uptake was 50% for Lp(a) compared to 84% for LDL. Oxidative modification of both Lp(a) and LDL was accompanied by a significant decrease in uptake and degradative capacities. Due to the limited uptake, native and oxidatively modified Lp(a) had only marginal effects on intracellular cholesterol metabolism, which was measured as inhibition of sterol synthesis and stimulation of cholesterol esterification. However, binding of Lp(a), oxidized Lp(a) and oxidized LDL to extracellular mesangial matrix was enhanced compared to LDL. Furthermore, incubation of mesangial cells with Lp(a) and oxLp(a) in concentrations of 2.5 micrograms/ml and higher resulted in a decrease of DNA synthesis. Regardless of the oxidative status, a maximal suppression of DNA synthesis was observed at 20 micrograms/ml Lp(a). Native Lp(a) also blunted the stimulatory effects of PDGF on mesangial cell DNA-synthesis. Lp(a) did not alter basal TGF-beta transcription in human mesangial cells. The avid interaction of Lp(a) and modified lipoproteins with mesangial matrix provides a concept for the enhanced entrapment of these lipoproteins in the diseased glomerulum. Native Lp(a) is a poor ligand for the LDL receptor; oxidation of Lp(a) even lowers the affinity towards this receptor. Further studies must be carried out to clarify the pathophysiological significance of Lp(a) trapping in the mesangial matrix.