Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context
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 cardiomy...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-02-01
|
| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419300118 |
| _version_ | 1818930332817162240 |
|---|---|
| author | Jia-Jung Lee Sin-Jhong Cheng Ching-Ying Huang Chen-Yun Chen Li Feng Daw-Yang Hwang Timothy J. Kamp Hung-Chun Chen Patrick C.H. Hsieh |
| author_facet | Jia-Jung Lee Sin-Jhong Cheng Ching-Ying Huang Chen-Yun Chen Li Feng Daw-Yang Hwang Timothy J. Kamp Hung-Chun Chen Patrick C.H. Hsieh |
| author_sort | Jia-Jung Lee |
| collection | DOAJ |
| description | 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 afterdepolarizations (DADs). Both the ADPKD patient iPSC-CMs showed more β-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. Fund: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Technology Supporting Platform Axis Scheme, Thematic Research Program and Summit Research Program, and Kaohsiung Medical University Hospital, Taiwan. Keywords: Human iPS cell, Autosomal dominant polycystic kidney disease, Cardiomyocyte, Arrhythmia |
| first_indexed | 2024-12-20T03:59:01Z |
| format | Article |
| id | doaj.art-bc5576960be141aaa38a3f419c8d4db7 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-20T03:59:01Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-bc5576960be141aaa38a3f419c8d4db72022-12-21T19:54:13ZengElsevierEBioMedicine2352-39642019-02-0140675684Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in contextJia-Jung Lee0Sin-Jhong Cheng1Ching-Ying Huang2Chen-Yun Chen3Li Feng4Daw-Yang Hwang5Timothy J. Kamp6Hung-Chun Chen7Patrick C.H. Hsieh8Ph.D. Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taiwan; Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanCellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Cardiology, Beijing AnZhen Hospital, Capital Medical University, Beijing, ChinaDivision of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanCellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United States; Department of Medicine, University of Wisconsin-Madison, Madison, WI, United StatesDivision of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Correspondence to: H. C. Chen, 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.Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States; Correspondence to: P. C.H. Hsieh, Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.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 afterdepolarizations (DADs). Both the ADPKD patient iPSC-CMs showed more β-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. Fund: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Technology Supporting Platform Axis Scheme, Thematic Research Program and Summit Research Program, and Kaohsiung Medical University Hospital, Taiwan. Keywords: Human iPS cell, Autosomal dominant polycystic kidney disease, Cardiomyocyte, Arrhythmiahttp://www.sciencedirect.com/science/article/pii/S2352396419300118 |
| spellingShingle | Jia-Jung Lee Sin-Jhong Cheng Ching-Ying Huang Chen-Yun Chen Li Feng Daw-Yang Hwang Timothy J. Kamp Hung-Chun Chen Patrick C.H. Hsieh Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context EBioMedicine |
| title | Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context |
| title_full | Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context |
| title_fullStr | Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context |
| title_full_unstemmed | Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context |
| title_short | Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytesResearch in context |
| title_sort | primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell derived cardiomyocytesresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419300118 |
| work_keys_str_mv | AT jiajunglee primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT sinjhongcheng primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT chingyinghuang primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT chenyunchen primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT lifeng primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT dawyanghwang primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT timothyjkamp primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT hungchunchen primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext AT patrickchhsieh primarycardiacmanifestationofautosomaldominantpolycystickidneydiseaserevealedbypatientinducedpluripotentstemcellderivedcardiomyocytesresearchincontext |