Wüthrich R P, Fan X, Ritthaler T, Sibalic V, Yu D J, Loffing J, Kaissling B
Division of Nephrology, University Hospital, and Institute of Physiology, University of Zürich-Irchel, Zürich, Switzerland.
Autoimmunity. 1998;28(3):139-50. doi: 10.3109/08916939808996282.
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 MRL-Fas(lpr) correlated with the enhanced Opn expression. Opn secretion in vitro by cultured renal tubular epithelial cells was upregulated by TNF-alpha and 1,25(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.
MRL-Fas(lpr)小鼠会自发发展出一种慢性狼疮样肾病，其特征为免疫复合物介导的肾小球肾炎以及间质中大量单核细胞浸润。在本研究中，我们探究了巨噬细胞趋化因子骨桥蛋白（Opn）在这种自身免疫性肾损伤小鼠模型中对巨噬细胞募集是否重要。我们检测了MRL-Fas(lpr)小鼠肾脏中Opn的表达，并将Opn的合成与巨噬细胞浸润程度相关联。免疫荧光染色显示，MRL-Fas(lpr)小鼠近端小管中有显著的Opn表达，而MRL-++对照小鼠中则没有。Northern印迹分析表明，与对照肾脏相比，MRL-Fas(lpr)肾脏中Opn mRNA的稳态转录水平也显著增加。此外，原位杂交显示MRL-Fas(lpr)小鼠近端小管中有大量Opn mRNA转录本，而对照小鼠中没有。MRL-Fas(lpr)小鼠肾脏中弥漫性的巨噬细胞浸润与Opn表达增强相关。培养的肾小管上皮细胞在体外分泌的Opn受TNF-α和1,25(OH)2-维生素D3上调，而在对照巨噬细胞系中未观察到调节作用。我们得出结论，肾小管细胞趋化分子Opn的表达增强是小鼠狼疮性肾炎的一个显著特征，可能是由MRL-Fas(lpr)中的促炎细胞因子环境所促进。Opn的慢性上调可能参与了MRL-Fas(lpr)小鼠肾脏中单核细胞的募集，从而促成自身免疫性肾病的发病机制。
