Oxidative stress plays an important role in the pathogenesis of anti-glomerular basement membrane antibody-induced
glomerulonephritis (
anti-GBM-GN).
Superoxide dismutase (SOD) is the first line of defense against oxidative stress by converting
superoxide to
hydrogen peroxide (H(2)O(2)). We investigated the effect of the SOD mimetic drug
tempol on
anti-GBM-GN in mice. 129/svJ mice were challenged with rabbit anti-mouse-GBM sera to induce GN and subsequently divided into
tempol (200 mg.kg(-1).day(-1), orally) and vehicle-treated groups. Routine histology, SOD and
catalase activities,
malondialdehyde (MDA), H(2)O(2), and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-kappaB, and
osteopontin were performed. Mice with
anti-GBM-GN had significantly reduced renal SOD and
catalase activities and increased H(2)O(2) and MDA levels. Unexpectedly,
tempol administration exacerbated
anti-GBM-GN as evidenced by intensification of
proteinuria, the presence of severe crescentic GN with leukocyte influx, and accelerated mortality in the treated group.
Tempol treatment raised SOD activity and H(2)O(2) level in urine, upregulated p65-NF-kappaB and
osteopontin in the kidney, but had no effect on renal
catalase activity. Thus
tempol aggravates
anti-GBM-GN by increasing production of H(2)O(2) which is a potent
NF-kappaB activator and as such can intensify
inflammation and renal injury. This supposition is supported by increases seen in p65-NF-kappaB,
osteopontin, and leukocyte influx in the kidneys of the
tempol-treated group.