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Inducible Nitric Oxide Synthase Inhibitors Reduce Urinary Markers of Systemic Oxidant Stress in Murine Proliferative Lupus Nephritis
  1. Chinedu J. Njoku,
  2. Kennerly S. Patrick,
  3. Philip Ruiz Jr,
  4. Jim C. Oates
  1. From the Department of Medicine (C.J.N., J.C.O.), Division of Rheumatology, Medical University of South Carolina, Charleston, SC; Department of Pharmaceutical Sciences (K.S.P.), Medical University of South Carolina, Charleston, SC; Department of Pathology (P.R.), University of Miami, Miami, FL. Supported by a research award from the Arthritis Foundation, Atlanta, GA, and grant numbers K08AR002193 and 5M01RR001070 from the National Institutes of Health, Bethesda, MD.
  1. Address correspondence to: Dr. Jim C. Oates, 96 Jonathan Lucas Street, Suite 912, PO Box 250637, Charleston, SC 29425; e-mail: oatesjc{at}


Background Proliferative lupus nephritis (PLN) is characterized by increased expression of inducible nitric oxide (NO) synthase (iNOS). Inhibition of iNOS with NG-monomethyl L-arginine (L-NMMA) abrogates renal disease in two models of murine PLN, but the mechanism of this effect is unknown. Reactive oxygen species have both direct and indirect pathogenic effects in inflammatory lesions and are therefore potentially an important therapeutic target in PLN. We hypothesized that inhibition of iNOS activity would reduce ROS production in murine PLN.

Methods A dose escalation of L-NMMA (0, 20, 100, and 500 mg/kg/day) was performed in New Zealand Black × New Zealand White F1 (NZB/W) mice with active renal disease. Twenty-four-hour urine nitrate + nitrite (NOX) was measured with a chemiluminescence NO analyzer. Twenty-four-hour urine 8-isoprostane F (8-iso-PGF2α) was measured by gas chromatography-negative ion chemical ionization mass spectrometry. MRL-MpJFASlpr (MRL/lpr) and NZB/W mice were divided into three groups and given either L-NMMA, L-N6-iminoethyl-lysine (L-NIL), or distilled water for 2 weeks. Urine NOX and 8-iso-PGF were determined after 2 weeks.

Results L-NMMA reduced both urine NOX and 8-iso-PGF levels in a dose-dependent fashion in NZB/W and MRL/lpr mice. Urine NOX and 8-iso-PGF levels were highly correlated. Both specific (L-NIL) and nonspecific (L-NMMA) iNOS inhibition reduced urine NOX and 8-iso-PGF levels in both models of murine PLN.

Conclusion These findings suggest that iNOS activity is a major source of reactive oxidant stress in these models of murine PLN. Future studies will address the pathogenic role of reactive oxygen stress in PLN.

Key Words
  • nitric oxide synthase
  • isoprostanes
  • lupus nephritis

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