Artemisinin analogue SM934 ameliorates the proteinuria and renal fibrosis in rat experimental membranous nephropathy
Artemisinin analogue SM934 ameliorates the proteinuria and renal fibrosis in rat experimental membranous nephropathy
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青蒿素类似物SM934改善大鼠实验性膜性肾病蛋白尿和肾纤维化
DOI：
10.1038/aps.2014.134
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发表时间：
2015-02-01
影响因子：
8.2
通讯作者：
Zuo, Jian-ping
中科院分区：
文献类型：
--
作者：
Li, Tian-tian;Zhang, Xiao-hui;Zuo, Jian-ping
目的：SM 934是一种新型的水溶性青蒿素衍生物，具有免疫调节活性，已被用于治疗小鼠狼疮性肾炎。方法：采用SD大鼠腹腔注射抗Fx 1A血清建立被动型Heymann肾炎（PHN）模型，观察SM 934对PHN的治疗作用。给大鼠口服SM 934（12.5和25 mg· kg-1· d-1）或泼尼松龙（5 mg· kg-1· d-1），连续28 d。采集血液和尿液样本以及肾脏组织进行分析。人补体C3 a诱导的HK-2细胞损伤被用于在体外experiments.Results：治疗PHN大鼠与SM 934或泼尼松龙减弱肾小球肾炎和肾纤维化的进展，证明了蛋白尿和循环抗体的水平降低，以及减少免疫复合物沉积，逆转足细胞损伤，并减弱肾小管间质纤维化的肾脏。此外，两种药物抑制TGF-β1表达和Smad 2/3磷酸化，并增加Smad 7表达。两种剂量的SM 934对PHN大鼠产生几乎相同的治疗效果。结论：SM 934通过下调TGF-β1/Smad信号通路，减轻PHN大鼠肾损伤，减轻肾小管间质纤维化。
Aim:SM934 is a novel water-soluble artemisinin derivative with immunoregulatory activities that has been used to treat murine lupus nephritis. In the current study, we investigated the effects of SM934 on rat experimental membranous nephropathy.Methods:Passive Heymann nephritis (PHN) was induced in SD rats by intraperitoneal injection of anti-Fx1A serum. The rats were orally administered SM934 (12.5 and 25 mg· kg− 1· d− 1) or prednisolone (5 mg· kg− 1· d− 1) for 28 d. Blood and urine sample, and kidney tissue were collected for analyses. Human complement C3a-induced injury of HK-2 cells was used for in vitro experiments.Results:Treatment of PHN rats with SM934 or prednisolone attenuated the progression of glomerulonephritis and renal fibrosis, as evidenced by the reduced level of proteinuria and circulating antibodies, as well as by the reduced immune complex deposition, reversed podocyte injuries, and attenuated tubulointerstitial fibrosis in the kidneys. Furthermore, the two drugs suppressed TGF-β1 expression and Smad2/3 phosphorylation, and increased Smad7 expression in the kidneys. The two doses of SM934 produced almost identical therapeutic effects on PHN rats. Pretreatment with SM934 or a C3a receptor antagonist blocked the C3a-induced epithelial-mesenchymal transition in HK-2 cells in vitro.Conclusion:SM934 ameliorates kidney injury and attenuates the tubulointerstitial fibrosis in PHN rats by down-regulation of the TGF-β1/Smad signaling pathway.