New insights into circulating cell-endothelium interactions and their significance for glomerular pathophysiology

Abstract

Neutrophil and monocyte infiltration of kidney glomeruli is a striking pathologic finding in the early stages of most forms of glomerulonephritis and appears to be an important determinant of glomerular injury. Recent research has permitted to clarify the mechanisms of leukocyte trafficking to inflamed glomeruli, which appear to involve several coordinated steps: chemotaxis along a concentration gradient of chemoattractants, adhesion to endothelial cells, diapedesis between endothelial cells, and interaction with resident renal cells. In glomerulonephritis, the deposition of immune complexes within glomerular capillaries triggers the local synthesis of chemotactic factors, including complement fragments, platelet-activating factor, leukotrienes, interleukin-8, and monocyte chemotactic protein-1, which promote attraction of neutrophils and monocytes within the glomerular tuft. Adhesion to resident glomerular cells, a critical step in the process of leukocyte infiltration, is a dynamic process that results from opposite factors: (1) shear forces generated by the movement of blood within the glomerular microcirculation that tend to detach inflammatory cells from the vascular wall and (2) adhesion glycoproteins expressed on the surface of leukocytes and endothelial cells, which are upregulated in human and experimental glomerulonephritis. It has been proposed that P-selectin, which is rapidly expressed on the surface of endothelial cells exposed to various stimuli, is a principal mediator of initial low-affinity binding of leukocytes (rolling). The tethering component mediated by P-selectin facilitates interaction of leukocytes with platelet-activating factor, a biologically active phospholipid that is rapidly synthesized by activated endothelial cells and is coexpressed with P-selectin on the endothelial cell plasma membrane. Platelet-activating factor ligates a receptor on leukocytes, serving as a signal for activation-dependent alteration in the β 2-integrins, lymphocyte function-associated antigen-1, and Mac-1, on leukocytes that makes them competent to bind to the counterreceptor intercellular adhesion molecule-1 on the endothelial cells. Such binding determines permanent attachment of leukocytes to endothelial cells. Cytokine-activated endothelial cells express other adhesive molecules, including E-selectin and vascular cell adhesion molecule-1, which both tether and activate leukocytes, contributing to their migration into extravascular tissues. In rats with nephrotoxic nephritis the simultaneous administration of anti-intercellular adhesion molecule-1 and anti-lymphocyte function-associated antigen-1 monoclonal antibodies prevents the development of proteinuria, the influx of inflammatory cells into the glomerular capillary tuft, and the subsequent crescent formation. These results raise the possibility that specific treatment aimed at blocking adhesive molecules might be used to limit the progression of glomerular injury in human glomerulonephritis.