Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling.
Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling.
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作者：
Czaya B;Heitman K;Campos I;Yanucil C;Kentrup D;Westbrook D;Gutierrez O;Babitt JL;Jung G;Salusky IB;Hanudel M;Faul C
血浆磷酸盐浓度升高（高磷血症）发生在慢性肾病（CKD）、某些遗传性疾病和摄入富含磷酸盐的饮食后。高磷血症和/或代谢调节因子的相关变化，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，我们报道与CKD患者相似，腺嘌呤诱导的CKD小鼠出现炎症、贫血和骨骼肌萎缩。这些并发症在喂食高磷酸盐饮食的小鼠中也可以观察到，即使没有CKD。消融病理性FGF23-FGFR4信号并不能保护增加磷酸盐饮食的小鼠或腺嘌呤诱导的CKD小鼠免受这些后遗症的影响。然而，低磷酸盐饮食改善了遗传性CKD小鼠模型中的贫血和骨骼肌萎缩。我们的体外机制研究表明，磷酸盐升高可诱导炎症信号传导并增加肝细胞中hepcidin的表达，这是高磷血症、贫血和骨骼肌功能障碍之间的潜在致病联系。我们的研究表明，由食用加工食品引起的高磷酸盐摄入，无论是否存在肾损伤，都可能产生有害影响，这不仅支持治疗CKD患者高磷血症的临床应用，也支持限制健康个体的磷酸盐摄入。
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.