Macrophages (M?) are integral in the pathogenesis of renal disease. Activated Mo induce apoptosis in resident renal cells. Mo rich infiltrates are characteristic of renal disease in the MRL-Faslpr strain with features that are similar to human lupus. Autoimmune renal disease in MKL-Faslpr mice is spontaneous, rapid and lethal, and is accompanied by a profound systemic illness. Thus, identifying molecules that regulate Mo numbers and functions in MRL-Faslpr kidneys is central to the pathogenesis of nephritis. Colony Stimulating Factor 1 (CSF-1) is a primary regulator of the Mo, responsible for survival, differentiation, and proliferation. There are 3 distinct CSF-1 isoforms; a cell surface glycoprotein, and two secreted isoforms; a glycoprotein and proteoglycan. Studies in transgenic mice that each only expresses an individual CSF-1 isoform indicate that there are distinct functions for each CSF-1 isoform during normal development. In light of the importance of CSF-1 in Mo mediated renal disease, it is critical to identify the local sites of CSF- 1 synthesis and functions of these CSF-1 isoforms during lupus nephritis. The actions of CSF-1 are exclusively mediated via the CSF-1 receptor (CSF-1R), principally on mononuclear phagocytes. However, CSF-IRs are on intrinsic renal cells, the tubular epithelial cell (TEC). Since TECs are a major source of CSF- 1 during renal inflammation, we suggest that CSF-1 mediated TEC mechanisms are pivotal in the pathogenesis of autoimmune renal disease. We hypothesize that CSF-1 isoforms have shared and unique roles in the pathogenesis of lupus nephritis. To test this hypothesis we propose to use novel genetically constructed mouse strains.
The specific aims are: 1) To determine whether CSF-1, and certain individual CSF-1 isoforms, promotes lupus nephritis and the systemic illness in MRL-Faslpr mice; and 2) To determine the role and location (renal, non-renal) of CSF-1, individual CSF-1 isoforms, and the CSF-lR's in the pathogenesis of lupus nephritis, and the systemic illness in MRL-Faslpr mice. Taken together, the proposed experiments will identify the potential role of CSF-1 isoforms in the pathogenesis of human lupus nephritis and the systemic illness.
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