Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310052, China; School of TCM, Hunan University of Chinese Medicine, China.
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310052, China.
Pharmacol Res. 2024 Oct;208:107392. doi: 10.1016/j.phrs.2024.107392. Epub 2024 Sep 2.
Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms METHODS: We applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted.
Hup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings.
Collectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN.
糖尿病肾病（DN）是糖尿病（DM）的一种主要并发症，目前尚无治愈方法。石杉碱甲（Hup A）是一种天然生物碱，具有显著的降血糖和抗炎作用。我们旨在研究 Hup A 对 DN 的保护作用，并探讨其潜在机制。
我们应用 STZ 诱导的糖尿病大鼠作为 DN 模型，并结合转录组、代谢组、微生物组和网络药理学（NP）进行综合分析。检测 Hup A 对 DN 的总作用（即尿蛋白、肾组织结构），并在糖尿病患者、db/db 小鼠和细胞水平上进一步验证差异基因。采用临床数据和小干扰 RNA（siRNA）-Apoe。
Hup A 减轻了 DN 大鼠的肾脏损伤。转录组学数据和 Western blot 表明，DN 的改善主要与 Apoe 和 Apoc2 有关。此外，代谢组学数据表明，Hup A 调节了 DN 诱导的脂质代谢紊乱，可能涉及鞘氨醇。Hup A 还丰富了微生物多样性，改善了 DN 诱导的微生物群落失衡。Spearman 相关分析表明，转录组、代谢组和微生物组之间存在显著相关性。Apoe 水平与 DN 患者的临床生物标志物呈正相关。Si-Apoe 在足细胞中也发挥保护作用。NP 分析还表明，Hup A 可能通过调节脂质代谢、微生物稳态和细胞凋亡来治疗 DN，进一步验证了我们的发现。
综上所述，我们首次提供了 Hup A 治疗 DN 的疗效证据，表明 Hup A 是预防和治疗 DN 的潜在药物。
