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Pim‐1 as a Therapeutic Target in Lupus Nephritis
Author(s) -
Fu Rong,
Xia Yong,
Li Meirong,
Mao Renxiang,
Guo Chaohuan,
Zhou Mianjing,
Tan Hechang,
Liu Meiling,
Wang Shuang,
Yang Niansheng,
Zhao Jijun
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40863
Subject(s) - lupus nephritis , anti dsdna antibodies , nephritis , peripheral blood mononuclear cell , medicine , systemic lupus erythematosus , immunology , antibody , immune system , glomerulonephritis , in vivo , autoimmune disease , lupus erythematosus , kidney , endocrinology , in vitro , biology , disease , biochemistry , microbiology and biotechnology
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. This study was undertaken to test the hypothesis that inhibition of Pim‐1 would have therapeutic potential in patients with LN. Methods Pim‐1 expression was analyzed in lupus‐prone (NZB × NZW)F1 mice (n = 6), human peripheral blood mononuclear cells (PBMCs) from SLE patients (n = 10), and glomeruli from patients with LN (n = 8). The therapeutic effect of the Pim‐1 inhibitor AZD1208 was assessed in the same murine lupus model (n = 10 mice per group). In vitro analysis was conducted to explore the mechanisms of action of Pim‐1 in mouse and human podocytes after Pim‐1 expression had been induced by anti–double‐stranded DNA (anti‐dsDNA) antibody–positive serum. Finally, MRL/lpr mice were used to confirm the therapeutic effects of Pim‐1 inhibition in vivo (n = 10 mice per group). Results Up‐regulation of Pim‐1 was seen in renal lysates from diseased (NZB × NZW)F1 mice and in PBMCs from patients with SLE and renal biopsy tissue from patients with LN, relative to their control counterparts (each P < 0.05). The Pim‐1 inhibitor AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti‐dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB × NZW)F1 mice (each P < 0.05 versus controls). Moreover, in mouse and human podocytes, Pim‐1 knockdown with targeted small interfering RNA (siRNA) suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti‐dsDNA–positive serum (each P < 0.05 versus control siRNA). Mechanistically, Pim‐1 modulated NLRP3 inflammasome activation through intracellular Ca 2+ ( P < 0.05 versus normal controls). 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 in patients with SLE. Targeting of the Pim‐1/NFATc1/NLRP3 pathway might therefore have therapeutic potential in human LN.