Treatment with a selective histone deacetylase 6 inhibitor decreases lupus nephritis in NZB/W mice (THER5P.910)

Abstract

Abstract To date, there are 17 histone deacetylase (HDAC) enzymes, divided into 4 classes, which alter protein function by removing acetyl groups from lysine residues. Prior studies report that non-selective HDAC inhibitors decrease disease in various lupus mouse models. Selective HDAC-6 inhibition acts on cytosolic proteins to decrease B cell proliferation and differentiation by inhibiting α-tubulin function. Since B cells play a critical role in the initiation and propagation of systemic lupus erythematosus, we hypothesized that a selective HDAC-6 inhibitor (HDAC6i) will alleviate disease in a mouse model. Intraperitoneal injections of HDAC6i (0.3 mg/kg, 1 mg/kg, or 3 mg/kg), vehicle control, or dexamethasone were administered to 21-week-old, female NZB/W mice, 5 days a week, for 13 weeks. Disease was evaluated by body weight, proteinuria, serum levels of anti-dsDNA antibody, cytokines and immunoglobulins, and post mortem evaluation of nephritis and B cell populations in the bone marrow and spleen. Treatment with HDAC6i decreased glomerular scores, spleen weights, and urine protein scores when compared to vehicle-treated mice. No differences in B cell development and differentiation in the bone marrow, and B cell activation in the spleen were noted. We conclude that HDAC-6 inhibitors are effective at decreasing lupus nephritis and disease in NZB/W mice, however further studies are warranted to investigate the underlying mechanism, particularly in regards to B cell pathophysiology.