Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN.
J Bone Miner Res. 2021 Jun;36(6):1117-1130. doi: 10.1002/jbmr.4272. Epub 2021 Mar 10.
Fibroblast growth factor-23 (FGF23) is a critical factor in chronic kidney disease (CKD), with elevated levels causing alterations in mineral metabolism and increased odds for mortality. Patients with CKD develop anemia as the kidneys progressively lose the ability to produce erythropoietin (EPO). Anemia is a potent driver of FGF23 secretion; therefore, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in clinical trials to elevate endogenous EPO to resolve anemia was tested for effects on iron utilization and FGF23-related parameters in a CKD mouse model. Mice were fed either a casein control diet or an adenine-containing diet to induce CKD. The CKD mice had markedly elevated iFGF23 and blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Cohorts of mice were then treated with a patient-equivalent dose of BAY 85-3934 (BAY; Molidustat), which elevated EPO and completely resolved aberrant complete blood counts (CBCs) in the CKD mice. iFGF23 was elevated in vehicle-treated CKD mice (120-fold), whereas circulating iFGF23 was significantly attenuated (>60%) in the BAY-treated CKD mice. The BAY-treated mice with CKD also had reduced BUN, but there was no effect on renal vitamin D metabolic enzyme expression. Consistent with increased EPO, bone marrow Erfe, Transferrin receptor (Tfrc), and EpoR mRNAs were increased in BAY-treated CKD mice, and in vitro hypoxic marrow cultures increased FGF23 with direct EPO treatment. Liver Bmp-6 and hepcidin expression were downregulated in all BAY-treated groups. Femur trabecular parameters and cortical porosity were not worsened with BAY administration. In vitro, differentiated osteocyte-like cells exposed to an iron chelator to simulate iron depletion/hypoxia increased FGF23; repletion with holo-transferrin completely suppressed FGF23 and normalized Tfrc1. Collectively, these results support that resolving anemia using a HIF-PHI during CKD was associated with lower BUN and reduced FGF23, potentially through direct restoration of iron utilization, thus providing modifiable outcomes beyond improving anemia for this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).
成纤维细胞生长因子 23（FGF23）是慢性肾脏病（CKD）的关键因素，其水平升高导致矿物质代谢改变和死亡率增加。随着肾脏逐渐丧失产生促红细胞生成素（EPO）的能力，CKD 患者会发生贫血。贫血是 FGF23 分泌的一个有力驱动因素；因此，目前正在临床试验中测试一种缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHI），以提高内源性 EPO 来解决贫血，以观察其对 CKD 小鼠模型中铁利用和 FGF23 相关参数的影响。将小鼠喂食酪蛋白对照饮食或含腺嘌呤饮食以诱导 CKD。CKD 小鼠的 iFGF23 和血尿素氮（BUN）、高磷血症和贫血显著升高。然后将小鼠分为几批，用相当于患者剂量的 BAY 85-3934（BAY；Molidustat）治疗，这提高了 EPO，并完全纠正了 CKD 小鼠异常的全血细胞计数（CBC）。在接受载体治疗的 CKD 小鼠中，iFGF23 升高（120 倍），而在接受 BAY 治疗的 CKD 小鼠中，循环 iFGF23 显著降低（>60%）。用 BAY 治疗的 CKD 小鼠的 BUN 也有所降低，但对肾脏维生素 D 代谢酶的表达没有影响。与 EPO 增加一致，BAY 治疗的 CKD 小鼠的骨髓 Erfe、转铁蛋白受体（Tfrc）和 EpoR mRNA 增加，缺氧骨髓培养物在直接 EPO 处理时增加 FGF23。肝 Bmp-6 和铁调素的表达在所有接受 BAY 治疗的组中均下调。用 BAY 给药不会使股骨小梁参数和皮质孔隙度恶化。在体外，用铁螯合剂处理分化的成骨细胞样细胞以模拟铁耗竭/缺氧会增加 FGF23；用全转铁蛋白补充完全抑制 FGF23 并使 Tfrc1 正常化。总的来说，这些结果支持在 CKD 期间使用 HIF-PHI 来解决贫血与较低的 BUN 和减少的 FGF23 有关，这可能是通过直接恢复铁利用来实现的，从而为该患者群体提供了除改善贫血以外的可改变的结果。 © 2021 美国骨矿研究学会（ASBMR）。
