Chemokine and chemokine receptor expression during initiation and resolution of immune complex glomerulonephritis

Chemokines participate in leukocyte infiltration, which plays a major role in glomerular injury during immune complex glomerulonephritis (IC-GN). Beca use target cell expression of chemokine receptors (CCR) is thought to media te leukocyte migration, the expression pattern of chemokines and CCR in a m odel of IC-GN was examined. The transient course and predominant glomerular pathology of this model allows the examination of both the induction and r esolution phases of IC-GN. GN was induced in mice by daily apoferritin inje ction for 2 wk. Urine samples and kidneys were obtained at 1, 2, and 4 wk. Albuminuria was noted at 2 wk, but resolved after 4 wk. This was associated with glomerular IC deposits and mesangial proliferation. Glomerular macrop hage infiltration was prominent at 1 and 2 wk, which resolved at 4 wk. Expr ession of monocyte chemoattractant protein-1 (MCP-1) and RANTES mRNA was up regulated at week 1 and decreased to control levels at weeks 2 and 4. The e xpression was localized to glomeruli by in situ hybridization and immunohis tochemistry. The mRNA of CCR1, CCR2, and CCR5 but not CCR3 or CCR4 were upr egulated at week 1 and decreased at weeks 2 and 4. Expression of CCR5 was l ocated to the glomerulus by in situ hybridization and quantitative reverse transcription-PCR of isolated glomeruli. In summary, in a model of transien t IC-GN, MCP-1 and RANTES and their receptors CCR1, CCR2, and CCR5 are expr essed early and are already downregulated at the peak of proteinuria and le ukocyte infiltration. Resolution of glomerulonephritis is associated with a return to baseline of chemokine and CCR expression. Therefore, it is concl uded that glomerular MCP-1 and RANTES production directs circulating leukoc ytes that express CCR1, CCR2, and CCR5 into the glomerulus. After initiatin g GN, MCP-1 and RANTES and their receptors are readily downregulated.