Successful treatment of lupus nephritis in MRL-lpr/lpr mice by inhibiting ornithine decarboxylase

Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of cellular polyamines, putrescine, spermidine and spermine. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ODC and thereby depletes putrescine and spermidine levels in vivo and in vitro. Previous studies in lupus-prone MRL-lpr/lpr mice treated with 1% DFMO in drinking water have been associated with improved lifespan, and reduced anti-DNA antibody production, lymphadenopathy, and splenic polyamine levels. Since glomerulonephritis is a major cause of morbidity and mortality in lupus, we studied the effect of DFMO on renal histology of MRL-lpr/lpr mice. Female BALB/c and MRL-+/+ mice were used as controls. Dose response studies revealed that 1.5% DFMO in drinking water had maximum therapeutic efficacy and produced a significant 79% increase in the median lifespan of a group of 20 mice compared to an equal number of controls (P < 0.001). Renal histologic studies were performed on kidney sections from four to five mice each from DFMO-treated and untreated groups at 12, 16, 20, 24 and 29 weeks of age. Sections were read blinded to duration and treatment and scored by four major histologic criteria (glomerulonephritis, interstitial inflammation, perivascular inflammation, and vasculitis) and showed significant reduction in all these parameters in DFMO-treated mice when compared to age- and sex-matched untreated mice of the same strain. DFMO treatment had no significant effect on pulmonary histologic findings on these mice. DFMO treatment reduced ODC activity and polyamine concentrations in treated mice. Basal ODC activity of 24-week-old untreated and DFMO-treated MRL-lpr/lpr mice was 142 ± 14 and 27 ± 6 pmol CO₂/mg protein/hr, respectively. Basal kidney ODC activity of normal BALB/c and MRL-+/+ mice was 78 ± 14 and 93 ± 21 pmol CO₂/mg protein/hr, respectively and indicated a constitutively high level of ODC activity in lupus-prone MRL-lpr/lpr mice compared to other strains. These data suggest an important role of endogenous polyamines in the tissue injury of lupus and suggest novel approaches to therapy of lupus-related renal disease.