薯蓣皂苷元通过下调 PAR-1 抑制慢性炎症减轻糖尿病肾病：体内和体外研究。
Sarsasapogenin alleviates diabetic nephropathy through suppression of chronic inflammation by down-regulating PAR-1: In vivo and in vitro study.
机构信息
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
Institute for Stem Cell and Neural Regeneration; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
出版信息
Phytomedicine. 2020 Nov;78:153314. doi: 10.1016/j.phymed.2020.153314. Epub 2020 Aug 26.
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-κB 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-κB 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-κB 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-κB, 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-κB, 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-κB by down-regulating PAR-1 in kidney.
背景
薯蓣皂素（Sar）通过抑制 NLRP3 炎性小体对糖尿病肾病（DN）有较好的疗效，但潜在机制尚不清楚。
目的
本研究旨在探讨凝血酶及其受体蛋白酶激活受体 1（PAR-1）对 DN 条件下 NLRP3 炎性小体和 NF-κB 信号通路的调节作用，并进一步阐述 Sar 对 DN 的分子机制。
方法
采用链脲佐菌素诱导糖尿病大鼠，连续 10 周给予 Sar（0、20 和 60mg/kg）灌胃。然后收集尿液和血清，用于测定反映肾功能的蛋白排泄、肌酐、尿素氮和尿酸，对肾组织切片进行过碘酸-希夫染色和 ki67 表达以反映细胞增殖，对肾皮质进行 NLRP3 炎性小体和 NF-κB 信号以及凝血酶/PAR-1 信号的检测。进一步采用高糖培养的人肾小球系膜细胞（HMCs）来研究 Sar 的作用和机制。
结果
Sar 显著改善了糖尿病大鼠的肾功能和系膜细胞增殖，抑制了肾皮质中 NLRP3 炎性小体和 NF-κB 的激活。此外，Sar 显著下调了肾皮质中 PAR-1 的蛋白和 mRNA 水平，但对肾脏中的凝血酶活性没有影响，尽管糖尿病大鼠肾皮质中的凝血酶活性明显降低。同时，高糖诱导了 NLRP3 炎性小体和 NF-κB 的激活，增加了 PAR-1 的表达，而对 HMCs 中的凝血酶活性没有影响；然而，Sar 共同处理改善了所有上述指标。进一步的研究表明，PAR-1 敲低减弱了 NLRP3 炎性小体和 NF-κB 的激活，而 Sar 的加入在高糖培养的 HMCs 中增强了这些作用。
结论
Sar 通过下调肾脏中的 PAR-1 缓解了大鼠的 DN，从而抑制了 NLRP3 炎性小体和 NF-κB。
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