Objective

Current treatment options for lupus are far from optimal. Previously, we reported that PI3K/AKT/mTOR, MEK1/Erk1, 2, p38, STAT3, STAT5, NF-κB, multiple Bcl-2 family members, and various cell cycle molecules were over-expressed 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 tested the therapeutic potential of this agent in murine lupus nephritis.

Methods

The synthetic triterpenoid CDDO-Me, or placebo, was administered to two month old B6. Sle1. Sle3 mice or MRL. lpr mice, which develop spontaneous lupus. All mice were phenotyped for disease.

Results

CDDO-Me-treated mice exhibited significantly reduced splenic cellularity, with decreased CD4+ T-cells and activated CD69+/CD4+ T-cells compared to the placebo-treated mice. These mice also exhibited significant reduction in serum autoantibody levels, including anti-dsDNA and anti-glomerular antibodies. Finally, CDDO-Me treatment attenuated renal disease in mice, as marked by reduced 24-hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO-Me treatment dampened MEK1/2, ERK, and STAT3 signaling within lymphocytes and oxidative stress. Importantly, the NF-E2-Related Factor 2 (Nrf2) pathway was activated after CDDO-Me treatment, indicating that CDDO-Me may be modulating renal damage in lupus via the inhibition of oxidative stress.

Conclusion

These findings underscore the importance of AKT/MEK1/2/NF-κB signaling in engendering murine lupus. Our studies reveal that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematological, autoimmune and pathological manifestations of lupus.