Astragalus membranaceus and Salvia miltiorrhiza ameliorates cyclosporin A-induced chronic nephrotoxicity through the "gut-kidney axis"
Astragalus membranaceus and Salvia miltiorrhiza ameliorates cyclosporin A-induced chronic nephrotoxicity through the "gut-kidney axis"
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DOI：
10.1016/j.jep.2020.113768
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发表时间：
2021-01-05
影响因子：
5.4
通讯作者：
Liu, Yao
中科院分区：
文献类型：
--
作者：
Han, Cong;Jiang, Yue-hua;Liu, Yao
民族药理学相关性：黄芪、丹参配伍是中医临床上广泛应用的治疗慢性肾脏病的有效方剂。我们前期的研究表明AS可以通过“肠-肾轴”缓解早期CKD，但AS在环孢菌素A诱导的慢性肾毒性（CICN）所致CKD中晚期“肠-肾轴”中的调节作用尚不清楚。探讨AS通过调节肠道植物群以进一步控制CICN中的miRNA-mRNA相互作用谱来发挥保护作用。将32只小鼠随机分为4组：正常组（N）（橄榄油组）、模型组（M）（CsA组，30 mg/kg·d）、AS组（CsA + AS组，30 + 8.4 g/kg·d）和FMT-AS组（CsA + AS组，30 mg/kg·d）。将小鼠处理6周。检测肾功能相关代谢物的变化，观察结肠和肾脏的病理变化，并对小鼠粪便进行16 S rDNA测序。此外，对肾脏进行miRNA和mRNA测序，以构建其他3组与M组相比的差异表达（DE）谱。然后预测DE miRNAs中的靶mRNA，并使用KEGG对DE mRNAs进行综合分析以注释基因功能。结果：M组8种可加重肾功能的代谢产物增加，伴有肾小球基底膜增厚、肾小管空泡变性和胶原纤维增生，而AS和FMT-AS干预均不同程度地改善了这些变化。同时，M组肠道通透性增加，植物群的丰富度和多样性降低，厚壁菌与拟杆菌的比值（F/B）增加。AS和FMT-AS处理逆转了植物群紊乱，增加了产丁酸和乳酸的益生菌，尤其是阿克曼氏菌和乳酸杆菌，它们可能调节了12条重叠的前20条KEGG通路，如丁酸代谢、色氨酸代谢和几条RF相关通路，从而缓解了肾代谢。最终筛选出15个DE miRNAs和45个DE mRNAs作为治疗靶点，其结果与测序结果一致。结论：AS通过“肠肾轴”减轻CICN引起的肾纤维化和代谢。Akkermansia和Lactobacillus等益生菌是主要的驱动因素，而miRNA-mRNA相互作用谱，尤其是丁酸代谢和色氨酸代谢，可能是重要的后续反应和调控机制。
Ethnopharmacological relevance: The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription that is widely used to treat chronic kidney disease (CKD) clinically in traditional Chinese medicine. Our previous studies have shown that AS can alleviate early CKD through the "gut-kidney axis", but the regulatory role of AS in the "gut-kidney axis" in the middle and late stages of CKD caused by cyclosporin A-induced chronic nephrotoxicity (CICN) has remained unclear.Aim of the study: To explore the protective effect of AS by regulating the intestinal flora to further control the miRNA-mRNA interaction profiles in CICN.Materials and methods: Thirty-two mice were divided into four groups: Normal (N) (olive oil), Model (M) (CsA, 30 mg kg(-1) d(-1)), AS (CsA + AS, 30 + 8.4 g kg(-1) d(-1)) and FMT-AS (CsA + Faeces of AS group, 30 mg + 10 mL kg(-1) d(-1)). The mice were treated for 6 weeks. Changes in renal function related metabolites were detected, pathological changes in the colon and kidney were observed, and 16S rDNA sequencing was performed on mouse faeces. In addition, miRNA and mRNA sequencing were performed on the kidney to construct differential expression (DE) profiles of the other 3 groups compared with group M. The target mRNAs among the DE miRNAs were then predicted, and an integrated analysis was performed with the DE mRNAs to annotate gene function by KEGG. DE miRNAs and DE mRNAs related to CICN in the overlapping top 20 KEGG pathways were screened and verified.Results: Eight metabolites that could worsen renal function were increased in group M, accompanied by thickening of the glomerular basement membrane, vacuolar degeneration of renal tubules, and proliferation of collagen fibres, while AS and FMT-AS intervention amended these changes to varying degrees. Simultaneously, intestinal permeability increased, the abundance and diversity of the flora decreased, and the ratio of Firmicum to Bacteroides (F/B) increased in group M. The AS and FMT-AS treatments reversed the flora disorder and increased probiotics producing butyric acid and lactic acid, especially Akkermansia and Lactobacillus, which might regulate the 12 overlapping top 20 KEGG pathways, such as Butanoate metabolism, Tryptophan metabolism and several RFrelated pathways, leading to the remission of renal metabolism. Finally, 15 DE miRNAs and 45 DE mRNAs were screened as the therapeutic targets, and the results coincided with the sequencing results.Conclusion: AS could alleviate renal fibrosis and metabolism caused by CICN through the "gut-kidney axis". Probiotics such as Akkermansia and Lactobacillus were the primary driving factors, and the miRNA-mRNA interaction profiles, especially Butanoate metabolism and Tryptophan metabolism, may be an important subsequent response and regulatory mechanism.