title: Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Texas Southwestern Medical Center at Dallas and University of Houston, Houston, Texas.
authors.forename: Tianfu
authors.initials: T
authors.lastname: Wu
authors.forename: Yujin
authors.initials: Y
authors.lastname: Ye
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Min
authors.forename: Jiankun
authors.initials: J
authors.lastname: Zhu
authors.forename: Elhaum
authors.initials: E
authors.lastname: Khobahy
authors.forename: Jason
authors.initials: J
authors.lastname: Zhou
authors.forename: Mei
authors.initials: M
authors.lastname: Yan
authors.forename: Sriram
authors.initials: S
authors.lastname: Hemachandran
authors.forename: Simanta
authors.initials: S
authors.lastname: Pathak
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000097:blood; D001806:Blood Urea Nitrogen; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008181:Lupus Nephritis / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D051057:Proto-Oncogene Proteins c-akt