Background/Purpose:  

Lupus nephritis (LN) is one of the main causes of morbidity and mortality in SLE. Although a combination therapy using steroids and immunosuppressant such as cyclophosphamide, azathioprine and mycophenolatemofetil has been well established in lupus nephritis, the therapy is often not effective. Establishment of new alternative therapy has been required. Proteasome inhibition by bortezomib has been recently expected to be a novel strategy for LN. However, the precise mechanisms of bortezomib for amelioration of LN have not fully been elucidated to date. Therefore, we conducted this study to clarify the mechanisms of the amelioration for the nephritis in the treatment with bortezomib.

Methods:  Bortezomib (0.75 mg/kg) 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 monitored every 3 weeks. The kidneys samples were examined histologically or used for real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis after 18 weeks of treatment. The peripheral blood mononuclear cells (PBMCs) were purified from spleen and used for real-time quantitative RT-PCR analysis. Serum cytokines levels were measured using flow cytometry. Anti-ds DNA antibody was measured by enzyme-linked immunoassays (ELISA). Immunohistochemical analysis was performed in the kidneys samples using antibodies to transforming growth factor (TGF)-β, angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R), type I collagen, immunoglobulin G, CD138 and CXCL-13.

Results:  Bortezomib reduced both the serum anti-dsDNA antibody titers and the proteinuria levels in the lupus prone mice. It prevented inflammatory cell infiltrations into and the deposition of immunoglobulin G within the glomeruli. Bortezomib reduced the interferon-g, interleukin (IL)-4, and IL-10 levels in both the serum and the ribonucleic acid expression levels for these cytokines in the PBMCs. Bortezomib reduced the number of CD 138 positive plasma cells in the glomeruli by downregulating CXCL-13. It prevented type I collagen synthesis by downregulating the expression of TGF-b, Ang II and AT1R, which are involved in renin-angiotensin system (RAS) related molecules.

Conclusion:  Bortezomib is an effective therapeutic reagent for LN through multiple mechanisms such as suppressive effects aginst cytokines production, chemokines production, antibodies production, and RAS. In particular, the suppressive effects on the formation of the fibrosis characterized by type I collagen synthesis by downregulating RAS related molecules may be beneficial in the treatment of refractory SLE patients who have refractory LN.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/bortezomib-treatment-prevents-glomerulosclerosis-associated-with-lupus-nephritis-in-a-murine-model-through-suppressive-effects-on-the-immune-and-renin-angiotensin-systems/