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Abstract Number: 1447

A Synthetic Triterpenoid CDDO-Me Prevents and Reverses Murine Lupus Nephritis

Tianfu Wu1, Yujin Ye1, Mei Yan1, Xin J. Zhou2, Michael Andreef3 and Chandra Mohan1, 1Division of Rheumatology/Internal Medicine, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, 2Internal Medicine - Rheumatic Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 3Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: lupus nephritis and signal transduction, T cells

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Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

T. Wu,
None;

Y. Ye,
None;

M. Yan,
None;

X. J. Zhou,
None;

M. Andreef,
None;

C. Mohan,
None.

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