Background/Purpose:

Current treatment options for lupus are far from optimal. Previously, we have reported that PI3K/AKT/mTOR, MEK1/Erk1,2, p38, STAT3, STAT5, NF-κB, multiple Bcl-2 family members, and various cell cycle molecules were overexpressed in splenic B-cells in an age-dependent and gene-dose-dependent manner in mouse strains with spontaneous lupus. As the synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate  (CDDO-Me) has been shown to inhibit AKT, MEK1/2, and NF-κB, and to induce caspase-mediated apoptosis, we proceeded to test the therapeutic potential of CDDO-Me on murine lupus.

Methods:

In a preventive study, CDDO-Me or placebo were administered to 2 month old B6.Sle1.Sle3 mice (n=10 per group) at a dose of 3mg/kg, 3 times a week for 2 months. In the treatment study, diseased NZM2410 (age = 7mo; n = 4-7 per group) were treated with CDDO-Me at a dose of 3mg/kg, 5 times a week for 2 months. Proteinuria, BUN, autoantibody levels, cellularity and renal disease were examined to determine the efficacy of this agent.  

Results:

Splenic cellularity was reduced after CDDO-me treatment. Particularly, the percentage of splenic CD4⁺ T cells was decreased (12.1 ± 0.35% vs 15.1 ± 1.2%, P = 0.021), while the percentage of CD8⁺ T cells was increased (9.73 ± 0.4% vs 6.8 ± 1.1%, P = 0.023) in the CDDO-Me treated group compared to the placebo group. In addition, CDDO-Me-treated mice exhibited significant reductions in serum autoantibody levels, including anti-dsDNA and anti-glomerular antibodies. Finally, CDDO-Me treatment attenuated renal disease in mice, as revealed by reduced 24-hour proteinuria, blood urea nitrogen, and glomerulonephritis. In order to confirm the therapeutic efficacy of CDDO-Me, we carried out a treatment study by administering CDDO-Me to a different lupus strain (NZM2410, age = 7mo; N = 4-7 per group) for a period of 2 months. These mice were already proteinuric at the beginning of the study. Once again, CDDO-Me was remarkably effective in improving survival, and reducing cellularity, circulating antibodies and proteinuria. Thus, we have established that CDDO-Me is therapeutically effective, even when administered after disease onset. In terms of the underlying molecular mechanisms, we demonstrated that CDDO-Me treatment dampened MEK1/2, ERK, and STAT3 signaling within lymphocytes. Importantly, the NF-E2-Related Factor 2 (Nrf2) pathway was activated after CDDO-Me treatment, indicating that CDDO-Me can attenuate renal damage in lupus via the inhibition of oxidative stress. Collectively, these findings underscore the importance of AKT/MEK1/2/NF-κB signaling in engendering murine lupus.

Conclusion:

CDDO-me may effectively prevent the hematological, autoimmune and pathological manifestations of lupus via the blockade of multiple signaling nodes and oxidative stress.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-synthetic-triterpenoid-cddo-me-prevents-and-reverses-murine-lupus-nephritis/