Yuko Matsuki-Muramoto1, Kazuhisa Nozawa1, Kaori Uomori1, Iwao Sekigawa2,3, Yoshinari Takasaki1. 1. a Department of Rheumatology , Juntendo University School of Medicine , Tokyo , Japan. 2. b Department of Internal Medicine and Rheumatology , Juntendo University Urayasu Hospital , Chiba , Japan , and. 3. c Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan.
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.
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: S Zmorzyński; S Popek-Marciniec; W Styk; M Wojcierowska-Litwin; I Korszeń-Pilecka; A Szudy-Szczyrek; S Chocholska; M Hus; A A Filip Journal: Biomed Res Int Date: 2020-06-06 Impact factor: 3.411