Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis

Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchy mal cells during kidney disease. To investigate whether MCP-1 promotes tubu lar and:or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and gl omeruli were severely damaged in the MCP-1-intact strain (day 7). MCP-1 tra nscripts increased fivefold in MCP-1-intact mice. MCP-1 was predominantly l ocalized within cortical tubules (90%), and most cortical tubules were dama ged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, the re was a marked reduction (>40%) in tubular injury in MCP-1-deficient mice (histopathology, apoptosis). MCP-1-deficient mice were not protected from g lomerular injury (histopathology, proteinuria, macrophage influx). Macropha ge accumulation increased adjacent to tubules in MCP-1-intact mice compared with MCP-1-deficient mice (70%, P < 0.005), indicating that macrophages re cruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysacch aride-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, pro motes TEC and not glomerular damage, and increases activated macrophages ad jacent to TEC that damage TEC during NSN. Therefore, we suggest that blocka ge of TEC MCP-1 expression is a therapeutic strategy for some forms of kidn ey disease.