Activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in the immune response; however, little is known of its role in immune-induced renal injury. In this study, we examine JNK signaling in the rat anti-glomerular basement membrane (GBM) disease model using CC-401, a specific JNK inhibitor. Animals were given CC-401, vehicle alone or no treatment starting before anti-GBM serum injection and continued treatment until killing. In acute disease, CC-401 blocked JNK signaling and reduced proteinuria in the first 24 h. The transient neutrophil influx seen at 3 h of disease was not affected, however. Continued CC-401 treatment suppressed glomerular and tubulointerstitial damage usually seen at 14 days. The protective effect may be due to modulation of macrophage activation, as CC-401 had no effect upon glomerular macrophage infiltration at day 14 despite the suppression of glomerular lesions and a marked reduction in renal tumor necrosis factor-alpha and inducible nitric oxide synthase messenger RNA levels. Treatment with CC-401 had no apparent effect on T cell or humoral immune responses. These studies suggest that JNK signaling promotes renal injury in acute and progressive rat anti-GBM disease. JNK inhibitors may be a novel therapeutic approach for the treatment of human glomerulonephritis.