Macrophages induce
acute renal injury in anti-glomerular basement membrane (GBM)
glomerulonephritis. This operates, in part, via activation of the
c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt
disease progression, including crescent formation, in a model of severe crescentic
anti-GBM glomerulonephritis. WKY rats were immunized with sheep
IgG and then injected with sheep
anti-GBM serum (day 0). Animals were treated with the JNK inhibitor,
CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant
proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe
glomerulonephritis at day 24 with renal impairment and worsening
proteinuria. These animals had severe glomerular lesions, with 60% of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in
mRNA levels of
TNF-alpha, iNOS, MMP-12, and
TGF-beta1. In contrast,
CC-401 treatment prevented renal impairment, suppressed
proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response.
CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (
interleukin-10 and
heme oxygenase-1). In addition,
IL-1 induced MMP-12 and
IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial protection against the progression of crescentic
anti-GBM glomerulonephritis, which may be, in part, due to inhibition of the macrophage proinflammatory response.