Enhanced Osteopontin Expression and Macrophage Infiltration in MRL-Fas^lpr Mice with Lupus Nephritis

Abstract

MRL-Fas^lpr mice spontaneously develop a chronic lupus-like renal disease, characterized by immune complex-mediated glomerulonephritis and abundant mononuclear cell infiltration in the interstitium. In the present study we have examined whether the macrophage chemoattractant osteopontin (Opn) could be important in the recruitment of macrophages in this murine model of autoimmune renal injury. We have examined the expression of Opn in the kidney of MRL-Fas^lpr mice and have correlated Opn synthesis with the degree of macrophage infiltration. Immunofluorescence staining revealed prominent expression of Opn by proximal tubules in MRL-Fas^lpr mice but not in MRL-++ control mice. Northern blot analysis demonstrated that steady-state transcript levels for Opn mRNA were also significantly increased in MRL-Fas^lpr kidneys compared with control kidneys. Furthermore, in situ hybridization showed massive Opn mRNA transcripts in proximal tubules in MRL-Fas^lpr mice but not in controls. The diffuse macrophage infiltration in the kidney of MKL-Fas^lpr correlated with the enhanced Opn expression. Opn secretion in vitro by cultured renal tubular epithelial cells was upregulated by TNF-α and l,25(OH)₂-vitamin D₃, whereas no regulation was observed in a control macrophage cell line. We conclude that the enhanced expression of the chemotactic molecule Opn by tubular cells is a prominent feature of murine lupus nephritis and might be promoted by the proinflammatory cytokine environment in MRL-Fas^lpr. The chronic upregulation of Opn could participate in the recruitment of monocytes in the kidney of MRL-Fas^lpr mice, thereby contributing to the pathogenesis of autoimmune renal disease.

Key Words:

• Lupus nephritis
• Mice
• Osteopontin
• Macrophages
• Cytokines