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Pim\u20101 regulates lymphocyte proliferation and activation. The role of Pim\u20101 in autoimmune disease remains unclear. This study was undertaken to test the hypothesis that inhibition of Pim\u20101 would have therapeutic potential in patients with LN.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pim\u20101 expression was analyzed in lupus\u2010prone (NZB \u00d7 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\u20101 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\u20101 in mouse and human podocytes after Pim\u20101 expression had been induced by anti\u2013double\u2010stranded DNA (anti\u2010dsDNA) antibody\u2013positive serum. Finally, MRL\/lpr mice were used to confirm the therapeutic effects of Pim\u20101 inhibition in vivo (n = 10 mice per group).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Up\u2010regulation of Pim\u20101 was seen in renal lysates from diseased (NZB \u00d7 NZW)F1 mice and in PBMCs from patients with SLE and renal biopsy tissue from patients with LN, relative to their control counterparts (each <jats:italic>P<\/jats:italic> &lt; 0.05). The Pim\u20101 inhibitor AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti\u2010dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB \u00d7 NZW)F1 mice (each <jats:italic>P<\/jats:italic> &lt; 0.05 versus controls). Moreover, in mouse and human podocytes, Pim\u20101 knockdown with targeted small interfering RNA (siRNA) suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti\u2010dsDNA\u2013positive serum (each <jats:italic>P<\/jats:italic> &lt; 0.05 versus control siRNA). Mechanistically, Pim\u20101 modulated NLRP3 inflammasome activation through intracellular Ca<jats:sup>2+<\/jats:sup> (<jats:italic>P<\/jats:italic> &lt; 0.05 versus normal controls). The therapeutic effect of Pim\u20101 blockade was replicated in MRL\/lpr mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data identify Pim\u20101 as a critical regulator of LN pathogenesis in patients with SLE. Targeting of the Pim\u20101\/NFATc1\/NLRP3 pathway might therefore have therapeutic potential in human LN.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40863","type":"journal-article","created":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T13:44:53Z","timestamp":1550756693000},"page":"1308-1318","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Pim\u20101 as a Therapeutic Target in Lupus Nephritis"],"prefix":"10.1002","volume":"71","author":[{"given":"Rong","family":"Fu","sequence":"first","affiliation":[{"name":"First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Xia","sequence":"additional","affiliation":[{"name":"Third Affiliated Hospital of Guangzhou Medical University  Guangzhou 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