Pim-1 as a therapeutic target in human lupus nephritis.

OBJECTIVE: Lupus nephritis (LN) is a major determinant of morbidity and mortality in systemic lupus erythematosus (SLE). Pim-1 regulates lymphocyte proliferation and activation. The role of Pim-1 in autoimmune disease remains unclear. Therefore, we hypothesize that Pim-1 inhibition would have therapeutic potential for LN.

METHODS: We first analyzed Pim-1 expression in lupus-prone NZB/W F1 mice (n=6), in human peripheral blood mononuclear cells (PBMCs) of SLE patients (n=10), and in the glomeruli of LN patients (n=8). The therapeutic effect of Pim-1 inhibitor AZD1208 was assessed in this lupus model (n=10/group). In vitro analysis was conducted to explore the mechanism of Pim-1 in mouse and human podocytes induced by anti-dsDNA antibody positive (anti-dsDNA+ ) serum. Finally, MRL/lpr mice were used to confirm the therapeutic effects of Pim-1 inhibition in vivo (n=10/group).

RESULTS: Pim-1 upregulation was seen in renal lysates of diseased NZB/W F1 mice, peripheral blood mononuclear cells and renal biopsies from SLE patients relative to their counterparts (all P<0.05). Pim-1 inhibitor AZD1208 reduced proteinuria, glomerulonephritis, renal immune complex deposits and serum anti-dsDNA antibody, concomitant with suppression of NFATc1 expression and NLRP3 inflammasome activation. Moreover, in mouse and human podocytes, Pim-1 knockdown suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti-dsDNA+ serum. Mechanistically, Pim-1 modulated NLRP3 inflammasome activation through intracellular Ca2+ . The therapeutic effect of Pim-1 blockade was replicated in MRL/lpr mice.

CONCLUSION: These data identify Pim-1 as a critical regulator of LN pathogenesis and targeting Pim-1/NFATc1/NLRP3 pathway might be a therapy for human LN. This article is protected by copyright. All rights reserved.