黄芪甲苷通过抑制芳香烃受体途径减轻硫酸吲哚酚诱导的肾小管上皮细胞损伤。
Astragaloside IV attenuates indoxyl sulfate-induced injury of renal tubular epithelial cells by inhibiting the aryl hydrocarbon receptor pathway.
机构信息
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Nephrology Department, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
出版信息
J Ethnopharmacol. 2023 May 23;308:116244. doi: 10.1016/j.jep.2023.116244. Epub 2023 Feb 9.
ETHNOPHARMACOLOGICAL RELEVANCE
Astragalus membranaceus Fisch. ex Bunge has long been used to treat chronic kidney disease (CKD) in China. However, the mechanism of action requires further study. Indoxyl sulfate accumulation is the key cause of CKD progression. The aryl hydrocarbon receptor (AhR) plays an essential role in the renal tubular injury induced by indoxyl sulfate (IS).
AIM
We explored the effects of Astragaloside IV (AS-IV), a minor component of the flowering perennial Astragalus membranaceus Fisch. ex Bunge, on AhR activity during IS-induced injury of renal tubular epithelial cells.
METHODS
C57BL/6 mice fed a 0.2% adenine diet (adenine + IS) and intraperitoneally injected with IS were used to study the protective effects of AS-IV, and specifically the effect on the AhR. In addition, apoptosis (annexin/PI), oxidative stress and the AhR pathway were investigated in IS-stimulated HK-2 cells treated with AS-IV. The binding of AS-IV to the AhR was assessed in a molecular docking analysis. AhR knockdown using AhR siRNA allowed determination of the effects of AS-IV in IS-stimulated HK-2 cells.
RESULTS
AS-IV inhibited tubulointerstitial injury in adenine + IS mice. While AS-IV did not reduce serum IS levels, it did inhibit AhR expression in the kidney. In IS-stimulated HK-2 cells, AS-IV also dramatically reduced apoptosis, decreased oxidative stress responses and inhibited the expression of the AhR pathway. The molecular docking analysis showed surface binding of AS-IV to the AhR. Following AhR knockdown in HK-2 cells, IS-induced apoptosis was reduced and could not be further reduced by AS-IV.
CONCLUSION
By targeting the AhR, AS-IV may alleviate IS-induced renal tubular injury, thus offering a novel therapeutic approach to the treatment of chronic renal failure.
民族药理学相关性
黄芪在中国长期以来一直被用于治疗慢性肾脏病（CKD）。然而，其作用机制需要进一步研究。硫酸吲哚酚（IS）的蓄积是 CKD 进展的关键原因。芳香烃受体（AhR）在 IS 诱导的肾小管损伤中发挥着重要作用。
目的
我们研究了黄芪甲苷（AS-IV），一种多年生黄芪的次要成分，对 IS 诱导的肾小管上皮细胞损伤过程中 AhR 活性的影响。
方法
采用 0.2%腺嘌呤饮食（腺嘌呤+IS）喂养 C57BL/6 小鼠，并腹腔内注射 IS，研究 AS-IV 的保护作用，特别是对 AhR 的作用。此外，还研究了 AS-IV 对 IS 刺激的 HK-2 细胞凋亡（Annexin/PI）、氧化应激和 AhR 通路的影响。采用分子对接分析评估 AS-IV 与 AhR 的结合。采用 AhR siRNA 敲低 AhR，观察 AS-IV 在 IS 刺激的 HK-2 细胞中的作用。
结果
AS-IV 抑制腺嘌呤+IS 小鼠的肾小管间质损伤。虽然 AS-IV 不能降低血清 IS 水平，但能抑制肾脏中的 AhR 表达。在 IS 刺激的 HK-2 细胞中，AS-IV 还能显著降低细胞凋亡，减少氧化应激反应，并抑制 AhR 通路的表达。分子对接分析显示 AS-IV 与 AhR 表面结合。在 HK-2 细胞中敲低 AhR 后，IS 诱导的细胞凋亡减少，而 AS-IV 不能进一步减少细胞凋亡。
结论
AS-IV 通过靶向 AhR，可能减轻 IS 诱导的肾小管损伤，为慢性肾衰竭的治疗提供新的治疗方法。
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