Verkaik Melissa, Oranje Maarten, Abdurrachim Desiree, Goebel Max, Gam Zeineb, Prompers Jeanine J, Helmes Michiel, Ter Wee Pieter M, van der Velden Jolanda, Kuster Diederik W, Vervloet Marc G, Eringa Etto C
Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands.
Physiol Rep. 2018 Apr;6(7):e13591. doi: 10.14814/phy2.13591.
The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs. 256 ± 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (-13% and -19%, respectively) as was the decay of cytosolic calcium during diastole (-15% and -21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, α-MHC/β-MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD-induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1-week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD.
绝大多数慢性肾脏病（CKD）患者在进入终末期肾病之前就过早死亡，主要原因是心血管疾病，其中心力衰竭是主要的临床表现。我们推测，CKD导致的血浆成纤维细胞生长因子23（FGF23）升高会损害心脏舒张和收缩功能。为了验证这一假设，对小鼠进行了5/6肾切除术（5/6Nx）或连续7天注射FGF23。术后6周，与假手术小鼠相比，5/6Nx小鼠的血浆FGF23水平更高（分别为720±31与256±3 pg/mL，P = 0.034）。与对照组相比，从5/6Nx和注射FGF23的动物分离出的心肌细胞在收缩期胞质钙升高减慢（分别为-13%和-19%），舒张期胞质钙衰减也减慢（分别为-15%和-21%）。此外，两组在收缩期胞质钙峰值含量均有类似程度的降低。尽管CKD或FGF23预处理动物的胞质钙含量较低，但两组心肌细胞的收缩参数未观察到变化。两组之间钙处理蛋白的表达和心肌肌钙蛋白I磷酸化相似。各组之间的血压、心脏重量与胫骨长度比值、α-肌球蛋白重链/β-肌球蛋白重链比值以及心房钠尿肽（ANF）mRNA表达，以及通过磁共振成像（MRI）测量的收缩和舒张功能均无差异。总之，CKD诱导血浆FGF23迅速升高，以及在模拟肾病模型和FGF23治疗1周后心肌细胞钙瞬变类似程度的降低，表明FGF23在CKD中部分介导了心肌细胞功能障碍。
