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肾脏病与透析肾移植杂志 ›› 2021, Vol. 30 ›› Issue (3): 239-245.DOI: 10.3969/j.issn.1006298X.2021.03.009

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受体交互作用蛋白激酶1抑制剂necrostatin-1治疗狼疮性肾炎的实验研究

  

  • 出版日期:2021-06-28 发布日期:2021-06-22

Experimental study of receptor interaction protein kinase 1 inhibitor (necrostatin-1) in treatment of lupus nephritis

  • Online:2021-06-28 Published:2021-06-22

摘要: 目的:探讨狼疮性肾炎(LN)中坏死性凋亡的机制和受体交互作用蛋白激酶1(receptor interaction protein kinase 1,RIPK1)抑制剂necrostatin1(Nec1)对疾病的疗效。
方法:体内实验应用MRL/lpr自发诱导的系统性红斑狼疮小鼠,19周龄时腹腔注射RIPK1抑制剂Nec1[35mg/(kg·d)]3周。检测血清肌酐、补体水平和尿蛋白肌酐比值变化,观察肾脏病理改变,检测坏死性凋亡相关蛋白表达变化。体外实验检测Nec1处理系膜细胞坏死性凋亡的变化,利用qRTPCR检测促炎因子表达变化。
结果:经Nec1治疗后,LN小鼠全身免疫炎症反应和肾脏损伤缓解,血清抗核抗体、抗双链DNA抗体滴度和尿蛋白,肌酐比值降低。体外实验发现,Nec1抑制系膜细胞坏死性凋亡和促炎因子释放。
结论:RIPK1抑制剂Nec1可抑制系膜细胞的坏死性凋亡,改善LN的症状。


关键词: 狼疮性肾炎,坏死性凋亡,necrostatin-1,系膜细胞

Abstract:

Objective:To explore the mechanism of necroptosis in lupus nephritis and the efficacy of receptor interaction protein kinase 1 (RIPK1) inhibitor necrostatin1(Nec1) in the treatment of lupus nephritis.
Methodology:MRL/lpr mice at the age of 19 weeks was injected intraperitoneally with Nec1 [35 mg/(kg·d)] for 3 weeks. Changes were detected in serum creatinine, complement levels and urine protein/creatinine ratio. Kidney pathological staining was used to observe kidney pathological changes and the changes in expression of necroptosisrelated proteins. In vitro,the expression of necroptosisrelated molecules in mesangial cells treated with Nec1 were measured. Changes in the expression of proinflammatory factors were detected by qRTPCR.
Results:The systemic immune inflammatory response and kidney damage of mice with lupus nephritis were alleviated after treatment with Nec1,serum antinuclear antibodies titers,antidoublestranded DNA antibody titers,and urine protein/creatinine ratio were decreased,and Nec1 inhibited mesangial cell necrosis and the release of proinflammatory factors in vitro.
Conclusion:RIPK1 inhibitor Nec1 can inhibit the necrotizing apoptosis of mesangial cells and relieve the symptoms of lupus nephritis.


Key words: lupus nephritis, necroptosis, necrostatin-1, mesangial cell