Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD
Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD
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DOI：
10.1172/jci.insight.123817
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发表时间：
2019-02-21
期刊：
影响因子：
8
通讯作者：
White, Kenneth E.
中科院分区：
文献类型：
--
作者：
Clinkenbeard, Erica L.;Noonan, Megan L.;White, Kenneth E.
磷酸尿激素FGF 23在慢性肾病（CKD）中升高。CKD患者人群中过早死亡的风险显著较高，心血管疾病（CVD）是CKD所有阶段的主要死亡原因。CKD患者中FGF 23升高与全因死亡率增加相关;然而，FGF 23是否与CKD患者的积极适应相关尚不清楚。为了测试FGF 23在CKD表型中的作用，将晚期成骨细胞/骨细胞条件性Dmpl-Fgf 23小鼠（Fgf 23（fl/fl）/Dmp 1-Cre（+/-））置于含腺嘌呤的饮食中以诱导CKD。血清分析显示，酪蛋白喂养的Cre（+）小鼠与酪蛋白饮食和Cre（-）基因型对照组相比，血清磷酸盐和血尿素氮（BUN）显著升高。与酪蛋白喂养的小鼠相比，腺嘌呤在Cre（-）小鼠中显著诱导了血清完整FGF 23，而腺嘌呤喂养的Cre（+）小鼠的血清完整FGF 23和C末端FGF 23以及骨Fgf 23 mRNA降低了90%。无论基因型如何，喂食腺嘌呤饮食的小鼠的甲状旁腺激素显着升高，这显着增加了中段皮质孔隙度。与饮食和基因型对照组相比，腺嘌呤喂养的Cre（+）心脏的超声心动图显示了严重的主动脉钙化和心脏肥大。因此，这些研究表明，骨FGF 23增加，虽然与CKD的不良结局相关，但对于保护免受组织磷酸盐升高的心肾后果是必要的。
The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23(fl/fl)/Dmp1-Cre(+/-)) was placed on an adeninecontaining diet to induce CKD. Serum analysis showed casein-fed Cre(+) mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre(-) genotype controls. Adenine significantly induced serum intact FGF23 in the Cre(-) mice over casein-fed mice, whereas Cre(+) mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre(+) hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate.