An influx of leukocytes is common to progressive kidney diseases. Targeting specific molecules responsible for recruitment of leukocytes into the kidney provides a therapeutic strategy for halting tissue progressive damage. Monocyte chemoattractant protein-1(MCP-1) belongs to a family of """"""""chemokines"""""""" which attract leukocytes to tissues targeted for inflammation. MCP-l is abundantly expressed by renal parenchymal cells during progressive renal injury. Blockade of MCP-l reduces the influx of activated macrophages, thereby sparing the tubules from macrophage mediated apoptotic destruction in acute nephrotoxic serum nephritis. The MRL-Faslpr model is appealing to identify therapeutic targets for progressive kidney disease since renal destruction is spontaneous, steadily progressive, predictable, fatal and shares features with human illnesses. Kidney disease in the MRL-Faslpr model is complex and consists of glomerular, tubular and peri-vascular damage, accompanied by an robust influx of macrophages and lymphocytes. MCP-1 is vigorously expressed in the MRL-Faslpr kidney prior to injury, and increases with advancing disease. We have constructed an MRL-Faslpr strain genetically deficient in MCP-1 and determined that mice lacking MCP-l live far longer than the wild-type strain. Using genetic approaches, we propose to test the hypothesis that MCP-1 is a therapeutic target for progressive autoimmune kidney disease. We propose to: 1) determine whether MCP-1 is required for autoimmune renal disease. We will establish whether MCP-1(-/-) deficient MRL-Faslpr mice are protected from kidney disease, and determine whether protection is exclusive to the kidney, or is systemic. 2) determine whether delivery of MCP-1 into the kidney amplifies or incites progressive renal disease. Using a retroviral gene transfer approach that provides for sustained delivery of MCP-l to a discrete area of the kidney, we propose to determine the impact of local MCP-1 expression on renal pathology, and to investigate whether MCP-1 restores pathology within a discrete area in MCP-l deficient MRL-Faslpr kidneys. We will establish whether MCP-1 is required for autoimmune nephritis in the NZM241O strain. 3) establish whether delivery of MCP-1 receptor antagonist (MCP-1ra) into the MRLFaslpr kidney prevents injury. We propose to: deliver MCP-lra to a discrete segment of the kidney using an ex vivo retroviral gene transfer and throughout the kidney using a lentiviral vector in vivo. We will establish the crucial period for MCP- 1 r blockade via a tetracycline transactivator system to switch delivery of MCP- ira """"""""on and off"""""""" at stages during the progression of nephritis. 4) establish the role of chemokines that share the CCR2 with MCP-1 in MRL-Faslpr mice. We propose to compare renal disease in MRL-Faslprstrains deficient in CCR2 and MCP-l to establish whether other MCPs are potential_therapeutic targets for kidney disease.
