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Sci Rep. 2016 Jul 15;6:30013. doi: 10.1038/srep30013.

Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.

Author information

1
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
2
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
3
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
4
Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto 615-8510, Japan.
5
Department of Artificial Kidneys, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
6
Department of Environmental and Health Sciences, Kyoto University School of Public Health, Kyoto 606-8501, Japan.
7
Division of Nephrology and Dialysis, Kitano Hospital The Tazuke Kofukai Medical Research Institute, Osaka 530-8480, Japan.
8
Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto 606-8501, Japan.
9
Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo 105-8470, Japan.
10
Clinical Research Center, Chiba University of Medicine, Chiba 260-8677, Japan.

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.

PMID:
27418197
PMCID:
PMC4945931
DOI:
10.1038/srep30013
[Indexed for MEDLINE]
Free PMC Article

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