Department of Pharmacology, College of Pharmacy, Inner Mongolian Medical University.
Department of Clinical Pharmacy, Ordos Central Hospital.
Proc Jpn Acad Ser B Phys Biol Sci. 2022;98(7):361-377. doi: 10.2183/pjab.98.019.
Previous studies showed that lanthanum hydroxide (LH) has a therapeutic effect on chronic kidney disease (CKD) and vascular calcification, which suggests that it might have clinical value. However, the target and mechanism of action of LH are unclear. Metabolomics of clinical samples can be used to predict the mechanism of drug action. In this study, metabolomic profiles in patients with end-stage renal disease (ESRD) were used to screen related signaling pathways, and we verified the influence of LH on the ROS-PI3K-AKT-mTOR-HIF-1α signaling pathway by western blotting and quantitative real-time RT-qPCR in vivo and in vitro. We found that ROS and SLC16A10 genes were activated in patients with ESRD. The SLC16A10 gene is associated with six significant metabolites (L-cysteine, L-cystine, L-isoleucine, L-arginine, L-aspartic acid, and L-phenylalanine) and the PI3K-AKT signaling pathway. The results showed that LH inhibits the ESRD process and its cardiovascular complications by inhibiting the ROS-PI3K-AKT-mTOR-HIF-1α signaling pathway. Collectively, LH may be a candidate phosphorus binder for the treatment of vascular calcification in ESRD.
先前的研究表明，氢氧化镧（LH）对慢性肾脏病（CKD）和血管钙化具有治疗作用，这表明它可能具有临床价值。然而，LH 的作用靶点和机制尚不清楚。临床样本的代谢组学可用于预测药物作用的机制。在这项研究中，我们使用终末期肾病（ESRD）患者的代谢组学图谱来筛选相关的信号通路，并通过体内和体外 Western blot 和定量实时 RT-qPCR 验证了 LH 对 ROS-PI3K-AKT-mTOR-HIF-1α信号通路的影响。我们发现 ESRD 患者的 ROS 和 SLC16A10 基因被激活。SLC16A10 基因与六个显著代谢物（L-半胱氨酸、L-胱氨酸、L-异亮氨酸、L-精氨酸、L-天门冬氨酸和 L-苯丙氨酸）和 PI3K-AKT 信号通路相关。结果表明，LH 通过抑制 ROS-PI3K-AKT-mTOR-HIF-1α 信号通路来抑制 ESRD 及其心血管并发症的发生。总之，LH 可能是治疗 ESRD 血管钙化的候选磷结合剂。
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