Endogenous glucocorticoids modulate experimental anti-glomerular basement membrane glomerulonephritis

The influence of endogenous glucocorticoids (GC) on glomerular injury was s tudied in a rat model of heterologous anti-glomerular basement membrane (GB M) glomerulonephritis (GN). Sprague-Dawley rats underwent adrenalectomy (AD X) or sham-operation 3 days prior to i.v. administration of both nephritoge nic (100 mu g/g) and subnephritogenic (50 mu g/g) doses of sheep anti-rat G BM globulin. Administration of a subnephritogenic dose of anti-GBM globulin resulted in GN in adrenalectomized animals only. Similarly, ADX performed prior to administration of anti-GBM in the nephritogenic dose range resulte d in exacerbation of GN compared with sham-operated animals (24 h protein e xcretion: 190.8 +/- 32.8 versus 42.5 +/- 2.6 mg/24 h; P < 0.005). In ADX an imals receiving subnephritogenic doses of anti-GBM injury was manifested by abnormal proteinuria (62.7 +/- 5.8 mg/24 h), accumulation of neutrophils w hich peaked at 6 h (7.2 +/- 1.37 neutrophils per glomerular cross-section ( neut/gcs)) and macrophage accumulation in glomeruli at 24 h (6.8 +/- 1.2 ma crophages/gcs). Sham-adrenalectomized animals given the same dose of anti-G BM globulin developed minimal or no glomerular injury: urinary protein excr etion (8.7 +/- 1.5 mg/24 h, P < 0.001); neutrophils (0.2 +/- 0.04 neutrophi ls/gcs, P < 0.001); macrophages (1.2 +/- 0.5 macrophages/gcs, P < 0.001). T he increased cellular recruitment to glomeruli in adrenalectomized animals was associated with glomerular endothelial P-selectin expression. P-selecti n expression was not detected in sham-operated rats after anti-GBM injectio n. Complement deposition in glomeruli was minimal in both groups. Physiolog ic GC replacement of ADX rats receiving subnephritogenic-dose anti-GBM reve rsed the observed susceptibility to GN development, with urinary protein ex cretion (7.8 +/- 1.12, P < 0.005) and no detectable P-selectin expression o r leucocyte accumulation in glomeruli. These results suggest that endogenou s GC modulate heterologous anti-GBM nephritis in rats and that this may be attributable, in part, to regulation of P-selectin expression.