FGF23 induces left ventricular hypertrophy
FGF23 induces left ventricular hypertrophy
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DOI：
10.1172/jci46122
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发表时间：
2011-11-01
影响因子：
15.9
通讯作者：
Wolf, Myles
中科院分区：
文献类型：
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作者：
Faul, Christian;Amaral, Ansel P.;Wolf, Myles
慢性肾脏病（CKD）是一种公共卫生流行病，可增加心血管疾病导致的死亡风险。左心室肥厚（LVH）是CKD患者心血管疾病的重要机制。FGF 23水平升高与CKD患者LVH和死亡率的风险增加有关，但这些风险是否代表FGF 23的因果效应尚不清楚。在此，我们报道了在一个大的、种族多样的CKD队列中，升高的FGF 23水平与LVH独立相关。FGF 23通过FGF受体依赖性激活钙调神经磷酸酶-NFAT信号通路引起离体大鼠心肌细胞病理性肥大，但这种作用不依赖于肾脏和甲状旁腺中FGF 23的共同受体klotho。在野生型小鼠中肌内或静脉内注射FGF 23导致LVH，并且klotho缺陷小鼠表现出升高的FGF 23水平和LVH。在已建立的CKD动物模型中，使用FGF受体阻滞剂治疗可减轻LVH，但未观察到血压变化。这些结果揭示了FGF 23在LVH发病机制中的klotho独立因果作用，并表明慢性升高的FGF 23水平直接导致CKD个体的高LVH率和死亡率。
Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intrarnyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.