title: Bortezomib treatment prevents glomerulosclerosis associated with lupus nephritis in a murine model through suppressive effects on the immune and renin-angiotensin systems.
abstract: OBJECTIVE
  To clarify the mechanisms underlying lupus nephritis (LN) amelioration following bortezomib treatment.
  
  
  METHODS
  Bortezomib was administered subcutaneously every 3 days to NZB/W F1 mice, and the serum anti-double stranded (ds) deoxyribonucleic acid (DNA) antibody titers and proteinuria levels were measured. The renal samples and the splenocytes were examined histologically or used for real-time quantitative reverse transcription-polymerase chain reaction analysis after 18 weeks of treatment. Serum cytokine and anti-dsDNA antibody levels were measured using flow cytometry and enzyme-linked immunoassays every 3 weeks. Transforming growth factor (TGF)-β, angiotensin II type-1 receptor (AT1R), and type I collagen expression levels in the glomeruli were evaluated using immunohistochemistry.
  
  
  RESULTS
  Bortezomib reduced the serum anti-dsDNA antibody titers and the proteinuria levels. It prevented inflammatory cell infiltrations into and the deposition of immunoglobulin G within the glomeruli. Bortezomib reduced the interferon-γ, interleukin (IL)-4, and IL-10 levels in the serum and the ribonucleic acid expression levels for these cytokines within the splenocytes. Bortezomib prevented type I collagen synthesis by downregulating TGF-β and AT1R expression in the glomeruli.
  
  
  CONCLUSIONS
  Bortezomib exerts multiple immunosuppressive effects and thus ameliorates LN. Furthermore, bortezomib can prevent glomerulosclerosis formation in NZB/W F1 mice through suppressive effects on the renin-angiotensin system.
authors.affiliation: a Department of Rheumatology , Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsuki-Muramoto
authors.affiliation: a Department of Rheumatology , Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nozawa
authors.affiliation: a Department of Rheumatology , Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Uomori
authors.affiliation: b Department of Internal Medicine and Rheumatology , Juntendo University Urayasu Hospital , Chiba , Japan , and.|c Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan.
authors.forename: Iwao
authors.initials: I
authors.lastname: Sekigawa
authors.affiliation: a Department of Rheumatology , Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
mesh_terms: D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007107:Immune System / Q000187:drug effects* / Q000502:physiology; D007074:Immunoglobulin G / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008181:Lupus Nephritis / Q000097:blood / Q000188:drug therapy*; D051379:Mice; D008814:Mice, Inbred NZB; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000069286:Bortezomib; D007371:Interferon-gamma
keywords: Bortezomib; Glomerulosclerosis; Lupus nephritis; NZB/W F1; Systemic lupus erythematosus