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

Background. Abnormalities in lipid and lipoprotein metabolism have been imp licated 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 m onocyte infiltration. However, the role of LDL and ox-LDL in the early mono cyte adhesion to glomerular endothelial cells (ECs) and associated intracel lular signaling mechanisms are not clearly understood. Methods. In this study, we examined the effect of LDL and ox-LDL on intrace llular 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 p reincubation of ECs with specific PTK inhibitors blocked ox-LDL-induced ICA M-1 message and monocyte adhesion. Whereas experimental maneuvers that inhi bit either protein kinase C activation (by PKC depletion or with inhibitors ) or Gi-protein-mediated pathways pertussis toxin sensitive had no effect o n ox-LDL-induced monocyte adhesion and ICAM-1 expression, cAMP-elevating co mpounds did not induce ICAM-1 or monocyte adhesion. Conclusions. The data indicate that ox-LDL, by stimulating monocyte adhesio n to the glomerular endothelium, may regulate monocyte infiltration within the glomerulus, supporting an early pathobiological role for atherogenic li poproteins in glomerular injury. The results suggest that the activation of specific PTK and associated si,signaling may, at least in part, play a cri tical role in ox-LDL-mediated endothelial-monocyte interaction-related even ts. The data suggest that the interventions aimed at modifying associated i ntracellular signaling events within the glomerulus may provide potential t herapeutic modalities in monocyte/macrophage-mediated glomerular disease.