A FUNCTIONAL-ROLE FOR OSTEOPONTIN IN EXPERIMENTAL CRESCENTIC GLOMERULONEPHRITIS IN THE RAT

This study examined whether osteopontin (OPN), a molecule with monocyt e chemotactic and adhesive activity, participates in macrophage-mediat ed renal disease. Accelerated anti-glomerular basement membrane glomer ulonephritis was induced in groups of six rats. Animals were treated w ith a neutralizing anti-OPN or an irrelevant control antibody over day s 0-7 (induction phase) or days 7-14 (established disease). Administra tion of the control antibody had no effect on the severity of the dise ase. In contrast, anti-OPN treatment significantly reduced glomerular injury (urinary protein excretion) and prevented a loss of renal funct ion (creatinine clearance) during the induction of disease. This was a ccompanied by a significant reduction in renal macrophage and T-cell a ccumulation, T-cell activation, and histological injury (glomerular hy percellularity, segmental lesions, crescents, and tubulointerstitial l esions). An important finding was that anti-OPN treatment of establish ed crescentic glomerulonephritis led to a significant reduction in glo merular injury and recovery of renal function in association with inhi bition of macrophage and T-cell accumulation, T-cell activation, and h istological damage. Anti-OPN treatment significantly inhibited the upr egulation of OPN and its ligand CD44 but demonstrated no effect on upr egulation of intercellular adhesion molecule-1 (ICAM-1) expression in the kidney. Interestingly, anti-OPN treatment significantly reduced sk in swelling and leukocyte infiltration in the delayed type hypersensit ivity response. However, anti-OPN treatment had no effect on the humor al immune response. In summary, this study has demonstrated that OPN p lays a functional role in macrophage and T-cell accumulation and renal damage in both the induction and progression of a rat model of cresce ntic glomerulonephritis. Thus, OPN may be of pathological importance i n human glomerulonephritis and in cell-mediated immune diseases genera lly.