Hyperphosphatemia Contributes to Cardiac Injury in Chronic Kidney Disease

项目摘要 慢性肾脏病（CKD）是一种健康流行病，会增加心血管疾病导致的死亡风险。 高磷酸盐血症和激素成纤维细胞生长因子（FGF）23血清水平升高是一种 CKD的标志，并与心脏损伤和死亡的风险增加有关。我们之前发现， 啮齿类动物，高磷酸盐饮食诱导的高磷酸盐血症升高血清FGF 23 在没有肾损伤的情况下，磷酸盐水平升高并导致心脏肥大，这表明磷酸盐升高 和/或FGF 23本身可能作为循环因子而损害心脏。无论磷酸盐 或FGF 23是否可以直接靶向心脏并诱导损伤尚不清楚。FGF 23主要由骨骼产生， 我们先前发现，FGF 23可以激活培养的心肌细胞中的特异性信号传导事件， 肥厚然而，FGF 23是否可以直接靶向体内心肌细胞仍然未知。基于 在全球FGFR 4缺失和药理学FGFR 4抑制研究中，我们最近将FGFR 4鉴定为 FGF 23受体是CKD动物模型中心脏肥大发展所必需的， 高磷酸盐饮食的小鼠。对于拟议的研究，我们已经产生了一种新的小鼠模型的心脏 肌细胞特异性FGFR 4缺失。通过腺嘌呤饮食诱导CKD或给予高浓度的 磷酸盐饮食，我们将能够确定心脏中的FGF 23/FGFR 4激活是否是心脏生长所必需的。 心脏损伤的发展。此外，磷酸盐对心肌细胞的直接影响尚未被证实。 研究至今。我们的初步工作表明，心肌细胞外磷酸盐水平升高， 肌细胞培养物诱导促炎信号传导和成骨基因程序。在这里，我们将确定 这些变化是否导致小鼠的病理性心脏重塑，包括心脏肥大，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， 在正常情况下，心脏中没有发现FGF 23的表达。据报道，在CKD中 心脏开始产生FGF 23然而，心脏来源的FGF 23是否能引起心脏重塑， 不清楚为了确定心脏FGF 23产生的后果，我们将产生一种新的小鼠模型， 心肌细胞特异性缺失FGF 23，然后给予高磷酸盐或腺嘌呤 饮食，以及心脏结构和功能的详细分析。总的来说，我们的研究旨在测试 假设高磷酸盐血症-本身以及在CKD的背景下-通过以下方式导致心脏损伤 诱导心脏中的FGF 23产生。FGF 23是一种有效的促肥大因子，与循环FGF 23一样， 旁分泌FGF 23可能通过FGFR 4直接靶向心肌细胞并诱导心肌损伤。我们推测 FGFR 4的药理学阻断可以抑制FGF 23对心脏的病理作用，从而起到治疗心脏病的作用。 作为预防或治疗CKD相关心脏损伤和延长生存期的新治疗策略。

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.