Fibroblast Growth Factor 23 Regulation and Acute Kidney Injury.
Fibroblast Growth Factor 23 Regulation and Acute Kidney Injury.
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作者：
Zhou W;Simic P;Rhee EP
成纤维细胞生长因子 23 (FGF23) 水平升高是急性肾损伤 (AKI) 不良后果的标志物和潜在介质。我们最近发现甘油-3-磷酸 (G-3-P)（一种糖酵解副产物）是一种肾源性因子，可循环至骨骼和骨髓并在缺血性 AKI 中触发 FGF23 产生。进一步证明，这种肾到骨信号传导轴需要骨髓中的 G-3-P 转化为溶血磷脂酸 (LPA)，然后通过 LPAR1 受体进行 LPA 信号传导。这些发现强调了在 FGF23 过量的情况下可能适合治疗靶向的离散步骤，尽管需要更多的工作来确定靶向特定酶和受体亚型的特异性和安全性。重要的是，初步代谢组学筛查发现肾静脉 G-3-P 和循环 FGF23 之间存在很强的相关性，该筛查是在接受选择性导管插入术的人类受试者中进行的，没有 AKI 患者。这就提出了一个问题：在肾功能较轻度或慢性衰退的患者中，或者在正常生理条件下，G-3-P是否也可能调节FGF23稳态——越来越多的文献强调了一系列传统上认为仅在细胞内发挥作用的循环代谢物的功能作用，这一问题得到了加强。
Elevated fibroblast growth factor 23 (FGF23) levels are markers, and potential mediators, of adverse outcomes in acute kidney injury (AKI). We recently identified glycerol-3-phosphate (G-3-P), a glycolysis byproduct, as a kidney-derived factor that circulates to bone and bone marrow and triggers FGF23 production in ischemic AKI. This kidney-to-bone signaling axis was further shown to require the conversion of G-3-P to lysophosphatidic acid (LPA) in bone marrow, followed by LPA signaling through the LPAR1 receptor. These findings highlight discrete steps potentially amenable to therapeutic targeting in conditions of FGF23 excess, although more work is required to determine the specificity and safety of targeting specific enzyme and receptor isoforms. Importantly, the initial metabolomic screen that identified a strong correlation between renal vein G-3-P and circulating FGF23 was conducted in human subjects undergoing elective catheterization, none with AKI. This raises the question of whether G-3-P might also modulate FGF23 homeostasis in patients with more mild or chronic decrements in kidney function, or under normal physiologic conditions—a question that is reinforced by a growing body of literature highlighting functional roles for a range of circulating metabolites traditionally thought to function exclusively inside cells.
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