INTERLEUKIN-1 RECEPTOR ANTAGONIST MODULATES THE PROGRESSION OF A SPONTANEOUSLY OCCURRING IGA NEPHROPATHY IN MICE

Cytokines, such as interleukin-1 (IL-1), may play a key role in the pa thogenesis of IgA nephropathy (IgAN). This study was conducted to eval uate the effects of IL-1 receptor antagonist (IL-1ra) in the treatment of a spontaneously occurring experimental IgAN in established phase. ddY mice (12/group) were injected twice daily with 3 mg/kg of IL-1ra, intraperitoneally, for 8 consecutive weeks. The placebo mice were inje cted with saline only. As normal controls, ddY mice, which were not tr eated with IL-1ra or saline, were killed at 6 weeks of age. Results sh owed a significant reduction of proteinuria in the IL-1ra-treated mice , compared with saline-treated mice (urinary albumin/creatinine, 0.24 +/- 0.04 v 0.39 +/- 0.03, P < 0.001). A significant improvement of ren al Cr-51-EDTA (ethylenediaminetetra-acetic acid) clearance was observe d in the IL-1ra-treated mice (t(1/2), 12 +/- 2.7 minutes, compared wit h saline-treated mice 25 +/- 2.0 minutes, P < 0.001). Similarly, serum levels of creatinine (1.0 +/- 0.4 v 2.4 +/- 0.3 mg/ dL, P < 0.001) an d urea nitrogen (46 +/- 6 v 58 +/- 2 mg/dL, P < 0.01) were significant ly lower in IL-1ra-treated mice than in saline-treated mice. In renal tissue studies, the IL-1ra-treated mice exhibited significantly decrea sed mesangial cell proliferation, compared with saline-treated mice (P < 0.001), as shown by light and electron microscopy. In addition, the IL-1ra-treated mice showed significantly lower glomerular expression of collagen type IV, fibronectin, laminin, and IL-6 (P < 0.001) than s aline-treated mice, although they still showed higher glomerular expre ssion of collagen type IV (P < 0.01), fibronectin (P < 0.01), laminin (P < 0.001), IL-1 (P < 0.001), and IL-6 (P < 0.01) than did normal con trol mice, Meanwhile, glomerular C3 deposition was significantly lower in IL-1ra-treated mice than in saline-treated mice (P < 0.001), These findings indicate that IL-1ra partially prevented the progression of spontaneously occurring IgAN in this experimental model. Data from the se experiments also confirm the pathogenic effects of IL-1 in the esta blished phase of IgAN in ddY mice. (C) 1997 by the National Kidney Fou ndation, Inc.