Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
J Mol Cell Cardiol. 2013 May;58:199-208. doi: 10.1016/j.yjmcc.2013.01.015. Epub 2013 Jan 30.
Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD). Although the leading cause of mortality in ADPKD is cardiovascular disease, the relationship between these conditions remains poorly understood. PC2 is an intracellular calcium channel expressed in renal epithelial cells and in cardiomyocytes, and is thus hypothesized to modulate intracellular calcium signaling and affect cardiac function. Our first aim was to study cardiac function in a zebrafish model lacking PC2 (pkd2 mutants). Next, we aimed to explore the relevance of this zebrafish model to human ADPKD by examining the Mayo Clinic's ADPKD database for an association between ADPKD and idiopathic dilated cardiomyopathy (IDCM). Pkd2 mutant zebrafish showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. In human ADPKD patients, we found IDCM to coexist frequently with ADPKD. This association was strongest in patients with PKD2 mutations. Our results demonstrate that PC2 modulates intracellular calcium cycling, contributing to the development of heart failure. In human subjects we found an association between ADPKD and IDCM and suggest that PKD mutations contribute to the development of heart failure.
PKD1 和 PKD2 基因突变导致常染色体显性多囊肾病(ADPKD),这两个基因编码多囊蛋白-1(PC1)和多囊蛋白-2(PC2)。尽管 ADPKD 的主要致死原因是心血管疾病,但这些疾病之间的关系仍知之甚少。PC2 是一种在肾脏上皮细胞和心肌细胞中表达的细胞内钙通道,因此推测其可调节细胞内钙信号并影响心脏功能。我们的首要目标是研究缺乏 PC2 的斑马鱼模型(pkd2 突变体)的心脏功能。接下来,我们旨在通过检查 Mayo 诊所的 ADPKD 数据库,研究这种斑马鱼模型与人类 ADPKD 的相关性,以探讨 ADPKD 和特发性扩张型心肌病(IDCM)之间的关联。pkd2 突变体斑马鱼的心脏输出量低且房室传导阻滞。分离的 pkd2 突变心脏显示出细胞内钙循环受损和钙交替。这些结果表明 pkd2 突变体存在心力衰竭。在人类 ADPKD 患者中,我们发现 IDCM 常与 ADPKD 同时存在。在 PKD2 突变患者中,这种关联最强。我们的结果表明 PC2 调节细胞内钙循环,导致心力衰竭的发生。在人类受试者中,我们发现 ADPKD 与 IDCM 之间存在关联,并提示 PKD 突变有助于心力衰竭的发生。