Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Physiol Rep. 2020 Jun;8(11):e14434. doi: 10.14814/phy2.14434.
Iron-deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor-23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) FG-4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 ("iFGF23"). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild-type mice were fed an adenine-containing diet to induce CKD, then injected with EPO or FG-4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG-4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein-6 (Bmp-6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF-PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.
缺铁性贫血是成纤维细胞生长因子 23（Fibroblast growth factor-23，FGF23）的有力刺激物。贫血、FGF23 升高和血清磷酸盐升高是慢性肾脏病（Chronic kidney disease，CKD）患者的重要死亡风险因素。然而，贫血对 CKD 患者循环中 FGF23 总水平的贡献尚不清楚。我们的目标是使用促红细胞生成素（Erythropoietin，EPO）和缺氧诱导因子脯氨酰羟化酶抑制剂（Hypoxia-inducible factor prolyl hydroxylase inhibitor，HIF-PHDi）FG-4592 研究 CKD 模型中铁处理的正常化对生物活性完整 FGF23（“iFGF23”）的产生和相关结果的影响。我们的假设是，在 CKD 模型中纠正普遍存在的贫血将降低循环 FGF23。野生型小鼠喂食含腺嘌呤的饮食以诱导 CKD，然后注射 EPO 或 FG-4592。CKD 小鼠贫血，EPO 改善红细胞指数，而 FG-4592 增加血清 EPO 和骨髓红细胞生成素（Erythroferrone，Erfe），降低肝脏铁蛋白、骨形态发生蛋白-6（Bone morphogenic protein-6，Bmp-6）和铁调素 mRNAs。在 CKD 小鼠中，对照小鼠的 iFGF23 明显升高，但在给予任何一种 ESA 后降低了 >70%，血清磷酸盐无变化。ESA 治疗还降低了肾纤维化标志物，增加了 Cyp27b1 并降低了 Cyp24a1 mRNA 表达。因此，使用 EPO 和 HIF-PHDi 改善 CKD 模型中的铁利用显著降低了 iFGF23，表明贫血是 FGF23 的主要驱动因素，而 CKD 患者铁利用的管理可能转化为矿物质代谢的可改变结局。
