机构：[a]Ph.D. Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taiwan[b]Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan[c]Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan[d]Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan[e]Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan[f]Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan[g]Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States[h]Department of Cardiology, Beijing AnZhen Hospital, Capital Medical University, Beijing, China临床科室心脏内科中心首都医科大学附属安贞医院[i]Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United States[j]Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
Background: Mutations in PKD1 or PKD2 gene lead to autosomal dominant polycystic kidney disease (ADPKD). The mechanism of ADPKD progression and its link to increased cardiovascular mortality is still elusive. Methods: We differentiated ADPKD patient induced pluripotent stem cells (iPSCs) to cardiomyocytes (CMs). The electrophysiological properties at the cellular level were analyzed by calcium imaging and whole cell patch clamping. Findings: The ADPKD patient iPSC-CMs had decreased sarcoplasmic reticulum calcium content compared with Control-CMs. Spontaneous action potential of the PKD2 mutation line-derived CMs demonstrated slower beating rate and longer action potential duration. The PKD1 mutation line-derived CMs showed a comparable dose-dependent shortening of phase II repolarization with the Control-CMs, but a significant increase in beating frequency in response to L-type calcium channel blocker. The PKD1-mutant iPSC-CMs also showed a relatively unstable baseline as a greater percentage of cells exhibited delayed after depolarizations (DADs). Both the ADPKD patient iPSC-CMs showed more beta-adrenergic agonist-elicited DADs compared with Control-CMs. Interpretation: Characterization of ADPKD patient iPSC-CMs provides new insights into the increased clinical risk of arrhythmias, and the results enable disease modeling and drug screening for cardiac manifestations of ADPKD. (C) 2019 The Authors. Published by Elsevier B.V.
基金：
Ministry of Science and Technology, TaiwanMinistry of Science and Technology, Taiwan [MOST 106-2811-B-001-036, 106-2319-B-001-003]; National Health Research InstitutesNational Health Research Institutes, JapanNational Health Research Institutes - Taiwan [EX106-10512SI]; Academia Sinica Program for Technology Supporting Platform Axis (TSPA) Scheme, Thematic Research Programand Summit Research Program; [MOST104-2314-B-037-066]; [MOST107-2314-B037-019-MY3]; [KMUH103-3M06]; [KMUH104-4M10]
第一作者机构：[a]Ph.D. Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taiwan[b]Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan[c]Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan[d]Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
通讯作者：
通讯机构：[b]Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan[c]Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan[d]Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan[e]Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan[g]Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States[j]Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States[*1]Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.[*2]Division of Nephrology, Kaohsiung Medical University Hospital, Faculty of Medicine, Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
医学