The role of interleukin-1 (IL-1) in the pathogenesis of experimental crescentic glomerulonephritis was investigated. Administration of the interleukin-1 receptor antagonist (IL-1ra) was used to block the action of IL-1 during disease development. Two groups of six rats were primed with rabbit IgG, followed five days later by injection of rabbit anti-GBM serum (day 0). Animals were treated with a constant infusion of recombinant human IL-1ra (plasma level approximately 100 to 200 ng/ml) or saline (untreated) from day -1 until being killed on day 14. Untreated animals exhibited severe proteinuria and development renal dysfunction shown by increased serum urea and serum creatinine and reduced creatinine clearance. In contrast, IL-1ra treated animals had significantly reduced proteinuria (IL-1ra vs. untreated, P < 0.05) and maintained normal renal function (IL-1ra vs. untreated, P < 0.05). Histologically, IL-1ra treatment markedly reduced glomerular hypercellularity, glomerular necrosis and crescent formation and almost completely abrogated tubular atrophy and fibrosis. IL-1ra treatment suppressed glomerular macrophage accumulation by 57% (P < 0.01), while macrophage accumulation in the interstitium was completely abrogated and immune activation of the interstitial T cell infiltrate was prevented. This study demonstrates that IL-1 plays a key role in the pathogenesis of anti-GBM glomerulonephritis, and blocking its effects may provide a novel therapeutic approach to the treatment of human progressive glomerulonephritis.

We sought to determine the importance of integrins for recovery after acute tubular injury and to investigate the signal transduction pathways for integrin effects on cell cycle regulation involving proliferation and apoptosis. Primary cultures of rat renal proximal tubule epithelial cells were exposed to a superoxide-generating system to induce injury in the absence of overt necrosis. Integrin function was antagonized by the integrin recognition sequence tetrapeptide Gly-Arg-Gly-Asp (GRGD) or monoclonal antibody to beta 1-integrin. Injured cells had reduced thymidine uptake compared with normal cells. The presence of GRGD during recovery from injury caused a further 44% reduction in DNA synthesis but did not affect DNA synthesis in normal cells. Injured cells had an increased proportion of apoptosis that was further accentuated by exposed to GRGD during recovery. Integrin antagonism also stimulated apoptosis in uninjured cells. To investigate signal transduction mechanisms for this effect of integrins, inhibitors and activators of protein tyrosine kinase (PTK) and protein kinase C (PKC) were evaluated. Activation of PKC stimulated cellular proliferation, whereas inhibitors of PKC and PTK had no significant effect. Genistein, a PTK inhibitor, induced apoptosis in normal cells, mimicking the effect of integrin inhibition. On the other hand, PMA, an activator of PKC, prevented cells from becoming apoptotic when exposed to injury plus GRGD. The phosphorylation status of intracellular proteins was evaluated by immunoblotting with antiphosphotyrosine antibody. A similar pattern of decreased phosphorylation was observed after either integrin inhibition, injury, both, or PTK inhibition. These findings suggest that kinase cascades are involved in the effects of integrins on renal epithelial cell proliferation and apoptosis. After injury, an interaction between cells and the extracellular matrix is required for cells to proliferate and contribute to repair rather than to enter an apoptotic pathway.

Deoxyspergualin is an immunosuppressive drug which is effective in both preventing allograft rejection and suppressing steroid-resistant acute rejection. This study was designed to determine whether deoxyspergualin could suppress the development of rapidly progressive crescentic glomerulonephritis in antigen-primed animals. Accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced by priming rats with rabbit immunoglobulin G (IgG), followed 5 days later by an injection of rabbit anti-rat GBM serum (day 0). Groups of five animals were treated with deoxyspergualin (5 mg/kg.day) or saline by daily ip injection from day 0 until euthanasia on days 1, 7, 14, or 21. Deoxyspergualin treatment resulted in a significant suppression of renal disease. Compared with saline-treated controls, deoxyspergualin treatment reduced proteinuria, resolved hematuria, and completely prevented a fall in creatinine clearance. Deposition of rabbit IgG along the GBM was unaffected by deoxyspergualin treatment, but glomerular deposition of rat IgG and C3 was significantly reduced from day 14 onwards, which was associated with a significant reduction of circulating rat anti-rabbit IgG. Deoxyspergualin treatment also produced a dramatic improvement in renal histology. Glomerular necrosis, fibrosis, and crescent formation were markedly suppressed, whereas tubulointerstitial lesions were completely prevented. This was associated with a marked suppression of mononuclear cell infiltration and activation. In the glomerulus, macrophage infiltration was suppressed by approximately 50%, whereas accumulation of macrophages and immune-activated (interleukin-2 receptor) T cells within the interstitium was almost completely abrogated by deoxyspergualin treatment. In conclusion, deoxyspergualin was found to be effective in suppressing the development of experimental crescentic glomerulonephritis in antigen-primed animals by acting on both the local cell-mediated response within the kidney and the systemic humoral immune response. Further work is warranted to determine whether this could be a useful drug for the treatment of human proliferative glomerulonephritis.

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