Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease
Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease
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DOI：
10.1016/j.kint.2019.07.026
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发表时间：
2019-12-01
影响因子：
19.6
通讯作者：
David, Valentin
中科院分区：
文献类型：
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作者：
Francis, Connor;Courbon, Guillaume;David, Valentin
缺铁、贫血、高磷血症和成纤维细胞生长因子23 （FGF23）升高是慢性肾脏疾病（CKD）常见且相关的并发症，与CKD进展、心血管疾病和死亡有关。柠檬酸铁是一种口服磷酸盐结合剂，可降低CKD患者的膳食磷酸盐吸收和血清FGF23浓度，同时增加铁储存和血红蛋白。在这里，我们使用Co14a3基因敲除的进行性CKD小鼠模型和年龄匹配的野生型小鼠，比较了柠檬酸铁给药与矿物质充足对照饮食的效果。柠檬酸铁被给予敲除小鼠四周，从六周龄开始，当他们有明显的CKD，或者从四周龄开始，当他们有早期的CKD。10周大的基因敲除小鼠在对照组饮食中表现出明显的缺铁、贫血、高磷血症、血清FGF23升高、高血压、肾功能下降和左心室收缩功能障碍。枸橼酸铁可挽救敲除小鼠的缺铁和贫血，无论治疗开始的时间如何。在给予柠檬酸铁的敲除小鼠中，FGF23的循环水平和骨表达降低，在早期CKD开始使用柠檬酸铁时观察到更明显的降低。柠檬酸铁仅在早期CKD开始时降低血清磷酸盐。虽然柠檬酸铁减轻了基因敲除小鼠的收缩功能障碍，而与开始治疗的时间无关，但柠檬酸铁的早期开始治疗也减少了肾纤维化和蛋白尿，改善了肾功能，延长了寿命。因此，在小鼠CKD病程早期开始柠檬酸铁治疗可降低FGF23，减缓CKD进展，改善心功能并显着提高生存率。
Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Co14a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.