Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid

Tianfu Wu, Yujin Ye, So Youn Min, Jiankun Zhu, Elhaum Khobahy, Jason Zhou, Mei Yan, Sriram Hemachandran, Simanta Pathak, Xin J. Zhou, Michael Andreeff, Chandra Mohan

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Current treatment options for lupus are far from optimal. Previously, we reported that phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, MEK-1/ERK-1,2, p38, STAT-3, STAT-5, 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. Since the synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) has been shown to inhibit AKT, MEK-1/2, 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 2-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 numbers of both CD4+ T cells and activated CD69+/CD4+ T cells compared to the placebo-treated mice. These mice also exhibited a significant reduction in serum autoantibody levels, including anti-double-stranded DNA (anti-dsDNA) and antiglomerular antibodies. Finally, CDDO-Me treatment attenuated renal disease in mice, as indicated by reduced 24-hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO-Me treatment dampened MEK-1/2, ERK, and STAT-3 signaling within lymphocytes and oxidative stress. Importantly, the NF-E2-related factor 2 pathway was activated after CDDO-Me treatment, indicating that CDDO-Me may modulate renal damage in lupus via the inhibition of oxidative stress.

CONCLUSION: These findings underscore the importance of AKT/MEK-1/2/NF-κB signaling in engendering murine lupus. Our findings indicate that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematologic, autoimmune, and pathologic manifestations of lupus.

Original languageEnglish (US)
Pages (from-to)3129-3139
Number of pages11
JournalArthritis & rheumatology (Hoboken, N.J.)
Volume66
Issue number11
DOIs
StatePublished - Nov 1 2014

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Lupus Nephritis
Oxidative Stress
Mitogen-Activated Protein Kinase Kinases
NF-E2-Related Factor 2
Inbred MRL lpr Mouse
Placebos
Phosphatidylinositol 3-Kinase
T-Lymphocytes
Kidney
Therapeutics
Blood Urea Nitrogen
Sirolimus
Caspases
Glomerulonephritis
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Proteinuria
Autoantibodies
Cell Cycle
B-Lymphocytes
Lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid. / Wu, Tianfu; Ye, Yujin; Min, So Youn; Zhu, Jiankun; Khobahy, Elhaum; Zhou, Jason; Yan, Mei; Hemachandran, Sriram; Pathak, Simanta; Zhou, Xin J.; Andreeff, Michael; Mohan, Chandra.

In: Arthritis & rheumatology (Hoboken, N.J.), Vol. 66, No. 11, 01.11.2014, p. 3129-3139.

Research output: Contribution to journalArticle

Wu, T, Ye, Y, Min, SY, Zhu, J, Khobahy, E, Zhou, J, Yan, M, Hemachandran, S, Pathak, S, Zhou, XJ, Andreeff, M & Mohan, C 2014, 'Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid', Arthritis & rheumatology (Hoboken, N.J.), vol. 66, no. 11, pp. 3129-3139. https://doi.org/10.1002/art.38782
Wu, Tianfu ; Ye, Yujin ; Min, So Youn ; Zhu, Jiankun ; Khobahy, Elhaum ; Zhou, Jason ; Yan, Mei ; Hemachandran, Sriram ; Pathak, Simanta ; Zhou, Xin J. ; Andreeff, Michael ; Mohan, Chandra. / Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid. In: Arthritis & rheumatology (Hoboken, N.J.). 2014 ; Vol. 66, No. 11. pp. 3129-3139.
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AU - Ye, Yujin

AU - Min, So Youn

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AU - Khobahy, Elhaum

AU - Zhou, Jason

AU - Yan, Mei

AU - Hemachandran, Sriram

AU - Pathak, Simanta

AU - Zhou, Xin J.

AU - Andreeff, Michael

AU - Mohan, Chandra

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N2 - OBJECTIVE: Current treatment options for lupus are far from optimal. Previously, we reported that phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, MEK-1/ERK-1,2, p38, STAT-3, STAT-5, 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. Since the synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) has been shown to inhibit AKT, MEK-1/2, 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 2-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 numbers of both CD4+ T cells and activated CD69+/CD4+ T cells compared to the placebo-treated mice. These mice also exhibited a significant reduction in serum autoantibody levels, including anti-double-stranded DNA (anti-dsDNA) and antiglomerular antibodies. Finally, CDDO-Me treatment attenuated renal disease in mice, as indicated by reduced 24-hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO-Me treatment dampened MEK-1/2, ERK, and STAT-3 signaling within lymphocytes and oxidative stress. Importantly, the NF-E2-related factor 2 pathway was activated after CDDO-Me treatment, indicating that CDDO-Me may modulate renal damage in lupus via the inhibition of oxidative stress.CONCLUSION: These findings underscore the importance of AKT/MEK-1/2/NF-κB signaling in engendering murine lupus. Our findings indicate that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematologic, autoimmune, and pathologic manifestations of lupus.

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