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

Hua Lu, Junhui Zhen, Tianfu Wu, Ai Peng, Ting Ye, Tao Wang, Xueqing Yu, Nosratola D. Vaziri, Chandra Mohan, Xin J. Zhou

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Abstract

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 2O2). 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), H2O2, and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-κB, and osteopontin were performed. Mice with anti-GBM-GN had significantly reduced renal SOD and catalase activities and increased H2O2 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 H2O2 level in urine, upregulated p65-NF-κB and osteopontin in the kidney, but had no effect on renal catalase activity. Thus tempol aggravates anti-GBM-GN by increasing production of H2O2 which is a potent NF-κB activator and as such can intensify inflammation and renal injury. This supposition is supported by increases seen in p65-NF-κB, osteopontin, and leukocyte influx in the kidneys of the tempol-treated group.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume299
Issue number2
DOIs
StatePublished - Aug 2010
Externally publishedYes

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Keywords

  • Catalase
  • Crescentic glomerulonephritis
  • Hydrogen peroxide
  • NF-κB
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Urology

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