title: Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.
abstract: Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca(2+) entry and gene expression profiles compared with those of iPSCs from non-ADPKD subjects. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed the correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that high serum MMP1 levels may be a novel risk factor. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ameku
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Taura
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.|Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto 615-8510, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Numata
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.|Department of Artificial Kidneys, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Shiota
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Toyoda
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsui
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Araoka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Yasuno
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Mae
authors.affiliation: Department of Environmental and Health Sciences, Kyoto University School of Public Health, Kyoto 606-8501, Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Division of Nephrology and Dialysis, Kitano Hospital The Tazuke Kofukai Medical Research Institute, Osaka 530-8480, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Kitaoka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Amano
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Arai
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichisaka
authors.affiliation: Department of Environmental and Health Sciences, Kyoto University School of Public Health, Kyoto 606-8501, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Environmental and Health Sciences, Kyoto University School of Public Health, Kyoto 606-8501, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Asaka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo 105-8470, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Ubara
authors.affiliation: Division of Nephrology and Dialysis, Kitano Hospital The Tazuke Kofukai Medical Research Institute, Osaka 530-8480, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Muso
authors.affiliation: Department of Artificial Kidneys, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukatsu
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Clinical Research Center, Chiba University of Medicine, Chiba 260-8677, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.|Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto 615-8510, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Environmental and Health Sciences, Kyoto University School of Public Health, Kyoto 606-8501, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Osafune
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002454:Cell Differentiation; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D002532:Intracranial Aneurysm / Q000097:blood / Q000473:pathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000097:blood*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000401:mortality / Q000473:pathology*; D012307:Risk Factors; D013345:Subarachnoid Hemorrhage / Q000473:pathology*; D050396:TRPP Cation Channels / Q000235:genetics
chemical_list: D015415:Biomarkers; D020781:Matrix Metalloproteinase 1; D050396:TRPP Cation Channels; C522360:MMP1 protein, human