Oxidized low-density lipoprotein stimulates monocyte adhesion to glomerular endothelial cells

Background. Abnormalities in lipid and lipoprotein metabolism have been implicated in the pathogenesis of glomerulosclerosis. Atherogenic lipoproteins for example, low-density lipoprotein (LDL) and oxidized LDL (ox-LDL)I have been shown to stimulate glomerular monocyte chemoattractants involved in monocyte infiltration. However, the role of LDL and ox-LDL in the early monocyte adhesion to glomerular endothelial cells (ECs) and associated intracellular signaling mechanisms are not clearly understood. Methods. In this study, we examined the effect of LDL and ox-LDL on intracellular signaling mechanisms associated with monocyte adhesion to glomerular ECs and intercellular adhesion molecule-1 (ICAM-1) expression. Results. Ox-LDL, but not LDL, stimulated EC ICAM-1 expression and monocyte adhesion. Ox-LDL elevated protein tyrosine kinase (PTK) activity, and the preincubation of ECs with specific PTK inhibitors blocked ox-LDL-induced ICAM-1 message and monocyte adhesion. Whereas experimental maneuvers that inhibit either protein kinase C activation (by PKC depletion or with inhibitors) or Gi-protein-mediated pathways pertussis toxin sensitive had no effect on ox-LDL-induced monocyte adhesion and ICAM-1 expression, cAMP-elevating compounds did not induce ICAM-1 or monocyte adhesion. Conclusions. The data indicate that ox-LDL, by stimulating monocyte adhesion to the glomerular endothelium, may regulate monocyte infiltration within the glomerulus, supporting an early pathobiological role for atherogenic lipoproteins in glomerular injury. The results suggest that the activation of specific PTK and associated si,signaling may, at least in part, play a critical role in ox-LDL-mediated endothelial-monocyte interaction-related events. The data suggest that the interventions aimed at modifying associated intracellular signaling events within the glomerulus may provide potential therapeutic modalities in monocyte/macrophage-mediated glomerular disease.