Intraglomerular leukocyte recruitment during nephrotoxic serum nephritis in rats

Although circulating phagocytic cells are important mediators of glomerular injury, their recruitment mechanisms are not completely understood. In this study, the intraglomerular trafficking of leukocytes was characterized in a rat model of acute glomerular injury induced by nephrotoxic serum (NTS). Polymorphonuclear (PMN) cells infiltrated, then disappeared rapidly, reaching a peak at 2 hr. By 6 hr the PMN migration had almost reversed but small numbers persisted until Day 7. The monocyte influx began almost simultaneously but was of lesser magnitude. However, the number of ED-1+ monocytes increased progressively from 60 min to reach a plateau by Day 2 and persisted to the end of the study (Day 28). Quantitation of intraglomerular Ia+ cells suggested in situ activation of monocytes within the glomeruli. Increased Ia+ cells were first evident on Day 2. By Day 5, 80% of the intraglomerular macrophages were Ia+. Complement depletion with cobra venom factor abrogated early albuminuria, delayed the initial PMN influx, but failed to attenuate monocyte migration. T lymphocytes appeared briefly between 10 min and 2 hr. In vitro proliferation study failed to demonstrate lymphocyte sensitization to glomerular basement membrane (GBM) antigens. A unique population of cells (OX19 OX8+), possibly representing natural killer cells, was present from Day 1 to Day 14. During the secondary wave of proteinuria (autologous phase), all leukocytes had disappeared except for macrophages and a small number of OX19-, OX8+ cells. A complex intraglomerular migration of leukocytes was triggered by the binding of nephrotoxic antibodies to GBM antigens. We speculate that this cascade involves several cell-to-cell interactions necessary for the full expression of glomerular injury.