Myeloperoxidase-Specific Plasma Cell Depletion by Bortezomib Protects from Anti-Neutrophil Cytoplasmic Autoantibodies–Induced Glomerulonephritis

Abstract

Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgGmediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.

Alterations in the Ubiquitin Proteasome System in Persistent but Not Reversible Proteinuric Diseases

“…Inhibition of proteasomal degradation could then exert beneficial effects in rodent MGN, which has been shown in animal models of stroke 38 and necrotizing crescentic GN. 39 However, despite reducing foot-process protein degradation, broad proteasomal inhibition increased proteinuria in PHN in our study, arguing for proteolysis by the UPS as a reparative rather than a causative mechanism Relative glomerular mRNA expression levels of nephrin and a-actinin-4 in POL glomeruli (n=6; day 2), PHN glomeruli (n=6; 14 days), or PAN glomeruli (n=6; 4 weeks) to respective controls. Values were normalized to 18S RNA as a housekeeping gene of the same preparations and are expressed as mean6SEM; no statistical significance was noted to respective controls (dashed gray line=1).…”

Association of Systemic Lupus Erythematosus Susceptibility Genes with IgA Nephropathy in a Chinese Cohort

“…UBE2L3 encodes a ubiquitin-conjugating enzyme involved in ubiquitin/proteasome-dependent degradation, which is important in the cell cycle, cell differentiation, apoptosis, sodium-channel function, and modulation of inflammatory responses. The ubiquitin/proteasome pathway has been suggested to be implicated in the development of multiple kidney diseases (53), and proteasome inhibitors have been efficacious in some forms of renal disorders, such as lupus nephritis (54), renal ischemia-reperfusion injury (55), and ANCA-induced GN (56). PXK encodes a multimodular protein composed of a phox homology domain, a protein kinase-like domain, and a WiskottAldrich syndrome protein homology 2 domain.…”

Membranous Nephropathy: Approaches to Treatment

“…Bortezomib, a proteasome inhibitor, has been shown to deplete autoreactive plasma cells and reduces antineutrophil cytoplasmic antibodies and anti-double-stranded DNA antibody titers in experimental models of antineutrophil cytoplasmic antibody-associated nephritis, and may be considered for the treatment of resistant MN [67,69]. The use of bortezomib can be associated with significant toxicity, but second-generation proteasome inhibitors with equal efficacy but improved safety profile, such as delanzomib and carfilzomib, are now available.…”