Pim-1 As a Therapeutic Target in Lupus Nephritis
Pim-1 As a Therapeutic Target in Lupus Nephritis
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Pim-1 作为狼疮性肾炎的治疗靶点
DOI：
10.1002/art.40863
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发表时间：
2019-07-02
影响因子：
13.3
通讯作者：
Zhao, Jijun
中科院分区：
文献类型：
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作者：
Fu, Rong;Xia, Yong;Zhao, Jijun
目的狼疮性肾炎（LN）是系统性红斑狼疮（SLE）发病和死亡的主要决定因素。Pim-1调节淋巴细胞增殖和活化。Pim-1在自身免疫性疾病中的作用尚不清楚。本研究旨在验证抑制Pim-1对LN患者具有治疗潜力的假设。方法检测狼疮易感（NZB x NZW）F1小鼠（n = 6）、SLE患者外周血单个核细胞（PBMCs）（n = 10）和LN患者肾小球（n = 8）Pim-1的表达。在相同的鼠狼疮模型中评估Pim-1抑制剂AZD 1208的治疗效果（每组n = 10只小鼠）。通过体外分析，以探讨Pim-1在小鼠和人足细胞中的作用机制，在Pim-1表达已被抗双链DNA（anti-dsDNA）抗体阳性血清诱导后。最后，使用MRL/lpr小鼠来确认体内Pim-1抑制的治疗效果（每组n = 10只小鼠）。结果Pim-1在（NZB × NZW）F1小鼠肾组织裂解液、SLE患者PBMC和LN患者肾活检组织中表达上调（P均< 0.05）。Pim-1抑制剂AZD 1208降低了患病（NZB x NZW）F1小鼠中蛋白尿、肾小球肾炎、肾免疫复合物沉积和血清抗dsDNA抗体水平的严重程度，同时抑制了NFATc 1表达和NLRP 3炎性小体激活（与对照组相比，P均< 0.05）。此外，在小鼠和人足细胞中，在抗dsDNA阳性血清存在下，靶向小干扰RNA（siRNA）敲低Pim-1抑制NFATc 1和NLRP 3炎性体信号传导（与对照siRNA相比，P均< 0.05）。机制上，Pim-1通过细胞内Ca 2+调节NLRP 3炎性小体活化（与正常对照相比P < 0.05）。在MRL/lpr小鼠中复制了Pim-1阻断的治疗效果。结论Pim-1在SLE患者LN发病中起重要调节作用。因此，靶向Pim-1/NFATc 1/NLRP 3通路可能在人LN中具有治疗潜力。
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 x 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 x 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 x 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 Ca2+ (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.