Arthritis Rheumatol:Pim-1作为人类狼疮性肾炎的治疗靶标

2019-02-25 xiangting MedSci原创

这些数据确定了Pim-1作为LN发病机制的关键调节因子,并且Pim-1/NFATc1/NLRP3通路可能是人类LN的治疗靶标。

狼疮性肾炎(LN)是系统性红斑狼疮(SLE)发病率和死亡率的主要决定因素。Pim-1调节淋巴细胞的增殖和活化。Pim-1在自身免疫性疾病中的作用仍不清楚。因此,这里假设抑制Pim-1对LN具有治疗潜力。

研究人员首先分析了狼疮易感NZB/W F1小鼠(n=6)、SLE患者人外周血单核细胞(PBMCs)(n=10)和LN患者肾小球(n=8)的Pim-1表达。在狼疮模型中评估了Pim-1抑制剂AZD1208的治疗效果(n=10/组)。进行体外分析以探讨Pim-1在抗dsDNA抗体阳性(抗dsDNA+)血清诱导的小鼠和人足细胞中的作用机制。最后,使用MRL/lpr小鼠证实体内Pim-1抑制的治疗效果(n=10/组)。

与对照相比,在患病NZB/W F1小鼠的肾裂解物、SLE患者外周血单核细胞和肾活检中观察到Pim-1上调(P均<0.05)。Pim-1抑制剂AZD1208减少蛋白尿、肾小球肾炎、肾免疫复合物沉积和血清抗dsDNA抗体,同时抑制NFATc1表达和NLRP3炎性体激活。此外,在小鼠和人足细胞中,敲除Pim-1在抗dsDNA+血清中抑制NFATc1和NLRP3炎性体的信号传导。从机制上来讲,Pim-1通过细胞内Ca2+调节NLRP3炎性体激活。阻断Pim-1的治疗效果在MRL/lpr小鼠中可以重复。

这些数据确定了Pim-1作为LN发病机制的关键调节因子,并且Pim-1/NFATc1/NLRP3通路可能是人类LN的治疗靶标。

原始出处:

Rong Fu. Pim‐1 as a therapeutic target in human lupus nephritis. Arthritis Rheumatol. 21 February 2019.

本文系梅斯医学(MedSci)原创编译整理,转载需授权!

 

 

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    2019-02-27 zhaojie88
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    2019-02-27 zhaojie88
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    2019-02-27 villahu

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