Sarsasapogenin alleviates diabetic nephropathy through suppression of chronic inflammation by down-regulating PAR-1: In vivo and in vitro study
Sarsasapogenin alleviates diabetic nephropathy through suppression of chronic inflammation by down-regulating PAR-1: In vivo and in vitro study
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DOI：
10.1016/j.phymed.2020.153314
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发表时间：
2020-11-01
期刊：
影响因子：
7.9
通讯作者：
Liu, Yao-Wu
中科院分区：
文献类型：
--
作者：
Tang, Zhuang-Zhuang;Zhang, Yu-Meng;Liu, Yao-Wu
背景：萨尔萨皂苷元通过抑制NLRP3炎症小体对糖尿病肾病有良好的治疗作用，但其可能的作用机制尚不清楚。目的：本研究旨在探讨凝血酶及其受体蛋白水解酶激活受体1(PAR-1)在糖尿病肾病中对NLRP3炎症小体及核因子-KB信号的调节作用，并进一步阐明其作用的分子机制。然后收集尿液和血清进行蛋白排泄、肌酐、尿素氮和尿酸测定以反映肾功能，肾组织切片进行过碘酸-席夫染色和Ki67表达以反映细胞增殖，肾皮质检测NLRP3炎症体和核因子-kappaB信号以及凝血酶/PAR-1信号。结果：丹参能明显改善糖尿病大鼠肾功能，促进系膜细胞增殖，抑制NLRP3炎性小体和肾皮质核因子-kappaB的活化。此外，虽然糖尿病大鼠肾皮质凝血酶活性显著降低，但SAR显著下调PAR-1蛋白和mRNA水平，但不影响肾脏凝血酶活性。同时，高糖诱导HMCS中NLRP3炎症体和核因子-kappaB的激活，PAR-1表达增加，而凝血酶活性无明显变化，但Sar联合治疗后上述指标均有改善。进一步的研究表明，PAR-1抑制高糖培养的HMC中NLRP3炎症小体和核因子-kappaB的激活，而Sar的加入则加强了这些作用。结论：Sar通过下调肾脏PAR-1抑制NLRP3炎性小体和NF-kappa B的表达，从而减轻糖尿病肾病的发生。
Background: Sarsasapogenin (Sar) shows good effects on diabetic nephropathy (DN) through inhibition of the NLRP3 inflammasome, yet the potential mechanism is not well known.Purpose: This study was designed to explore the regulation of thrombin and/or its receptor protease-activated receptor 1 (PAR-1) on the NLRP3 inflammasome and NF-KB signaling in DN condition, and further expounded the molecular mechanism of Sar on DN.Methods: Streptozotocin-induced diabetic rats were treated by gavage with Sar (0, 20 and 60 mg/kg) for consecutive 10 weeks. Then urine and serum were collected for protein excretion, creatinine, urea nitrogen, and uric acid assay reflecting renal functions, renal tissue sections for periodic acid-Schiff staining and ki67 expression reflecting cell proliferation, and renal cortex for the NLRP3 inflammasome and NF-kappa B signaling as well as thrombin/PAR-1 signaling. High glucose-cultured human mesangial cells (HMCs) were used to further investigate the effects and mechanisms of Sar.Results: Sar markedly ameliorated the renal functions and mesangial cell proliferation in diabetic rats, and suppressed activation of the NLRP3 inflammasome and NF-kappa B in renal cortex. Moreover, Sar remarkably down-regulated PAR-1 in protein and mRNA levels but didn't affect thrombin activity in kidney, although thrombin activity was significantly decreased in the renal cortex of diabetic rats. Meanwhile, high glucose induced activation of the NLRP3 inflammasome and NF-kappa B, and increased PAR-1 expression while didn't change thrombin activity in HMCs; however, Sar co-treatment ameliorated all the above indices. Further studies demonstrated that PAR-1 knockdown attenuated activation of the NLRP3 inflammasome and NF-kappa B, and Sar addition strengthened these effects in high glucose-cultured HMCs.Conclusion: Sar relieved DN in rat through inhibition of the NLRP3 inflammasome and NF-kappa B by down-regulating PAR-1 in kidney.