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

• Published in: Scientific reports Vol. 6; no. 1; p. 30013
• Main Authors: Ameku, Tomonaga, Taura, Daisuke, Sone, Masakatsu, Numata, Tomohiro, Nakamura, Masahiro, Shiota, Fumihiko, Toyoda, Taro, Matsui, Satoshi, Araoka, Toshikazu, Yasuno, Tetsuhiko, Mae, Shin-Ichi, Kobayashi, Hatasu, Kondo, Naoya, Kitaoka, Fumiyo, Amano, Naoki, Arai, Sayaka, Ichisaka, Tomoko, Matsuura, Norio, Inoue, Sumiko, Yamamoto, Takuya, Takahashi, Kazutoshi, Asaka, Isao, Yamada, Yasuhiro, Ubara, Yoshifumi, Muso, Eri, Fukatsu, Atsushi, Watanabe, Akira, Sato, Yasunori, Nakahata, Tatsutoshi, Mori, Yasuo, Koizumi, Akio, Nakao, Kazuwa, Yamanaka, Shinya, Osafune, Kenji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2016; Nature Publishing Group
• Subjects: 13/100; 13/31; 13/44; 13/51; 38/23; 38/61; 38/77; 631/532/2064/2158; 692/4022/1585/1589; 692/499; 82/80; Aged; Animals; Biomarkers - blood; Cell Differentiation; Cells, Cultured; DNA Methylation - genetics; Female; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Intracranial Aneurysm - blood; Intracranial Aneurysm - pathology; Male; Matrix Metalloproteinase 1 - biosynthesis; Matrix Metalloproteinase 1 - blood; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; multidisciplinary; Polycystic Kidney, Autosomal Dominant - mortality; Polycystic Kidney, Autosomal Dominant - pathology; Risk Factors; Science; Science (multidisciplinary); Subarachnoid Hemorrhage - pathology; TRPP Cation Channels - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep30013

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.