青蒿素类似物SM934改善大鼠实验性膜性肾病的蛋白尿和肾纤维化。
Artemisinin analogue SM934 ameliorates the proteinuria and renal fibrosis in rat experimental membranous nephropathy.
作者信息
Li Tian-tian, Zhang Xiao-hui, Jing Jing-feng, Li Xin, Yang Xiao-qian, Zhu Feng-hua, Tang Wei, Zuo Jian-ping
机构信息
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
出版信息
Acta Pharmacol Sin. 2015 Feb;36(2):188-99. doi: 10.1038/aps.2014.134. Epub 2015 Jan 26.
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.
目的
SM934是一种具有免疫调节活性的新型水溶性青蒿素衍生物，已用于治疗小鼠狼疮性肾炎。在本研究中，我们调查了SM934对大鼠实验性膜性肾病的影响。
方法
通过腹腔注射抗Fx1A血清在SD大鼠中诱导被动性Heymann肾炎（PHN）。大鼠口服给予SM934（12.5和25mg·kg⁻¹·d⁻¹）或泼尼松龙（5mg·kg⁻¹·d⁻¹），持续28天。收集血液、尿液样本和肾脏组织进行分析。使用人补体C3a诱导的HK-2细胞损伤进行体外实验。
结果
用SM934或泼尼松龙治疗PHN大鼠可减轻肾小球肾炎和肾纤维化的进展，蛋白尿和循环抗体水平降低、免疫复合物沉积减少、足细胞损伤逆转以及肾脏肾小管间质纤维化减轻均证明了这一点。此外，这两种药物抑制了肾脏中TGF-β1的表达和Smad2/3的磷酸化，并增加了Smad7的表达。两种剂量的SM934对PHN大鼠产生了几乎相同的治疗效果。用SM934或C3a受体拮抗剂预处理可在体外阻断C3a诱导的HK-2细胞上皮-间质转化。
结论
SM934通过下调TGF-β1/Smad信号通路改善PHN大鼠的肾损伤并减轻肾小管间质纤维化。
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