Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States.
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States.
Elife. 2022 Mar 18;11:e74782. doi: 10.7554/eLife.74782.
Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here, we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia, and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia, and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.
血浆磷酸盐浓度升高（高磷酸盐血症）发生在慢性肾脏病（CKD）、某些遗传疾病以及摄入富含磷酸盐的饮食后。高磷酸盐血症和/或代谢调节剂的相关变化，包括成纤维细胞生长因子 23（FGF23）的升高，是否直接导致 CKD 的特定并发症尚不确定。在这里，我们报告说，类似于 CKD 患者，腺嘌呤诱导的 CKD 小鼠会发生炎症、贫血和骨骼肌消耗。即使没有 CKD，高磷酸盐饮食也会导致这些并发症在小鼠中发生。病理性 FGF23-FGFR4 信号的缺失并不能保护高磷酸盐饮食的小鼠或腺嘌呤诱导的 CKD 小鼠免受这些后果的影响。然而，低磷酸盐饮食可改善 CKD 遗传小鼠模型中的贫血和骨骼肌消耗。我们的体外机制研究表明，磷酸盐升高可诱导肝细胞中的炎症信号和铁调素表达增加，这是高磷酸盐血症、贫血和骨骼肌功能障碍之间的潜在因果关系。我们的研究表明，高磷酸盐摄入（如摄入加工食品引起）可能有害，而与预先存在的肾损伤无关，这不仅支持了治疗 CKD 患者高磷酸盐血症的临床实用性，也支持了限制健康人群磷酸盐摄入的观点。
