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.

Keywords:

• Bortezomib
• Glomerulosclerosis
• Lupus nephritis
• NZB/W F1
• Systemic lupus erythematosus

Conflict of interest

The authors thank Dr. Hiroshi Koide, Tomomi Ikeda, and Takako Ikegami of the Laboratory of Molecular and Biochemical Research, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan, and Dr. Shinji Nakamura, Yuko Kojima, Yasuko Toui, and Katsumi Miyahara of the Laboratory of Morphology and Image Analysis, Juntendo University Graduate School of Medicine, Tokyo, Japan, for their technical assistance and support during this study.