Hyperphosphatemia Contributes to Cardiac Injury in Chronic Kidney Disease

项目总结 慢性肾脏疾病(CKD)是一种健康流行病，会增加因心血管疾病而死亡的风险。 高磷血症和血清成纤维细胞生长因子23激素水平升高是一种 这是慢性肾脏病的标志，与心脏损伤和死亡的风险增加有关。我们之前发现，在 啮齿动物，高磷饮食引起的高磷血症使血清FGF23升高 在没有肾脏损害的情况下，水平和引起心肌肥厚，提示磷酸盐升高 和/或FGF23本身可能作为循环因子而损害心脏。然而，无论磷酸盐 或者FGF23是否可以直接靶向心脏并导致损伤尚不清楚。FGF23主要由骨骼产生， 我们先前发现FGF23可以激活培养的心肌细胞中的特定信号事件，并诱导 肥大。然而，FGF23是否可以在体内直接靶向心肌细胞仍是未知的。基于 全球FGFR4缺失和药理学FGFR4抑制研究，我们最近发现FGFR4是 FGF23受体在慢性肾脏病动物模型心肌肥厚发生中的作用 在高磷饮食的小鼠身上。在拟议的研究中，我们建立了一种新的小鼠心脏模型 FGFR4的肌细胞特异性缺失。通过腺嘌呤饮食诱导CKD或通过给药高- 通过磷酸盐饮食，我们将能够确定心脏中是否需要激活FGF23/FGFR4 心脏损伤的发展。此外，磷酸盐对心肌细胞的直接影响尚未见报道。 到目前为止一直在研究。我们的初步工作表明，心脏细胞外磷酸盐水平的升高 心肌细胞培养诱导促炎信号和成骨基因程序。在这里，我们将确定 这些变化是否会导致小鼠的病理性心脏重构，包括心肌肥大，纤维化， 炎症和钙化。我们还发现，磷酸盐处理培养的心肌细胞可诱导 正常情况下心脏中不存在FGF23的表达。据报道，在CKD中 心脏开始产生FGF23。然而，心脏来源的FGF23是否会导致心脏重构， 不清楚。为了确定心脏FGF23产生的后果，我们将产生一个新的小鼠模型 心肌细胞特异性缺失FGF23，然后给予高磷或腺嘌呤 饮食，以及对心脏结构和功能的详细分析。总体而言，我们的研究旨在测试 假设高磷血症本身以及在慢性肾脏病的背景下，通过以下方式促进心脏损伤 诱导心脏产生FGF23。FGF23是一种强有力的促肥大因子，与循环中的FGF23一样， 旁分泌FGF23可能通过FGFR4直接靶向心肌细胞，导致心肌损伤。我们假定 药物阻断FGFR4可以抑制FGF23对心脏的病理作用，从而起到 作为预防或治疗CKD相关心脏损伤和延长生存期的一种新的治疗策略。

PROJECT SUMMARY Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to cardiovascular disease. Hyperphosphatemia and elevations in serum levels of the hormone fibroblast growth factor (FGF) 23 are a hallmark of CKD and associated with an increased risk of cardiac injury and death. We previously found that in rodents, hyperphosphatemia induced by the administration of a high-phosphate diet elevates serum FGF23 levels and causes cardiac hypertrophy in the absence of kidney damage, suggesting that elevated phosphate and/or FGF23 per se might act as circulating factors that can damage the heart. However, whether phosphate or FGF23 can directly target the heart and induce injury is unknown. FGF23 is mainly produced by bone, and we previously found that FGF23 can activate specific signaling events in cultured cardiac myocytes and induce hypertrophy. However, whether FGF23 can directly target cardiac myocytes in vivo remains unknown. Based on global FGFR4 deletion and pharmacological FGFR4 inhibition studies, we have recently identified FGFR4 as the FGF23 receptor that is required for the development of cardiac hypertrophy in animal models of CKD as well as in mice on high-phosphate diet. For the proposed study we have generated a novel mouse model for the cardiac myocyte-specific deletion of FGFR4. By inducing CKD via an adenine diet or by administration of a high- phosphate diet, we will be able to determine whether FGF23/FGFR4 activation in the heart is required for the development of cardiac injury. Furthermore, direct effects of phosphate on cardiac myocytes have not been studied to date. Our preliminary work indicates that elevations of extracellular phosphate levels in cardiac myocyte cultures induce pro-inflammatory signaling and osteogenic gene programs. Here we will determine whether these changes lead to pathologic cardiac remodeling in mice, including cardiac hypertrophy, fibrosis, inflammation and calcification. We also found that phosphate treatments of cultured cardiac myocytes induce the expression of FGF23 that under normal conditions is not found in the heart. It has been reported that in CKD the heart starts to produce FGF23. However, whether heart-derived FGF23 can cause cardiac remodeling, is unclear. To determine the consequences of cardiac FGF23 production, we will generate a new mouse model with cardiac myocyte-specific deletion of FGF23, followed by the administration of high-phosphate or adenine diets, and a detailed analysis of cardiac structure and function. Overall, our study is designed to test the hypothesis that hyperphosphatemia - by itself as well as in the context of CKD - contributes to cardiac injury by inducing FGF23 production in the heart. FGF23 is a potent pro-hypertrophic factor, and like circulating FGF23, paracrine FGF23 might directly target cardiac myocytes via FGFR4 and induce cardiac injury. We postulate that pharmacologic blockade of FGFR4 can inhibit the pathologic actions of FGF23 on the heart and thereby serve as a novel therapeutic strategy to prevent or treat CKD-associated cardiac injury and prolong survival.