Superoxide dismutase mimetic drug tempol aggravates anti-GBM antibody-induced glomerulonephritis in mice

Oxidative stress plays an important role in the pathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBMGN). Superoxide dismutase (SOD) is the first line of defense against oxidative stress by converting superoxide to hydrogen peroxide ([H.sub.2][O.sub.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 x [kg.sup.-1] x [day.sup.-1], orally) and vehicle-treated groups. Routine histology, SOD and catalase activities, malondialdehyde (MDA), [H.sub.2][O..sub.2], and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-[kappa]B, and osteopontin were performed. Mice with anti-GBM-GN had significantly reduced renal SOD and catalase activities and increased H202 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.sub.2][O.sub.2] level in urine, upregulated p65-NF-[kappa]B and osteopontin in the kidney, but had no effect on renal catalase activity. Thus tempol aggravates antiGBM-GN by increasing production of [H.sub.2][O.sub.2] which is a potent NF-[kappa]B activator and as such can intensify inflammation and renal injury. This supposition is supported by increases seen in p65-NF-[kappa]B, osteopontin, and leukocyte influx in the kidneys of the tempol-treated group. oxidative stress; catalase; hydrogen peroxide; crescentic glomerulonephritis; NF-[kappa]B doi: 10.1152/ajprenal.00583.2009.