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July 19, 2016

A new model for kidney disease

Doctors are unable to differentiate which AKPKD patients have a high risk for aneurysms. A new iPS cell model indicates MMP1 could be used to identify these patients.

The Osafune lab uses iPS cells to find a new marker for the risk of aneurysms that occur in kidney disease.

Cystic fibrosis and sickle cell anemia are well known monogenic diseases - diseases caused by a single defective gene, but the most common is one much harder to run off the tongue, autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by a single mutation in one of two genes, and estimates have millions of people suffering from the disease. ADPKD is marked by the formation of cysts in the kidneys that in many cases leads to severe renal failure that require dialysis or transplantation. Because it is genetic, the disease is believed to initiate before birth, but symptoms generally do not reveal themselves until well into adulthood.

Although ADPKD primarily affects the kidney, its pathology will spread to other organs. "Intracranial aneurysms [ICA] are a serious concern in ADPKD patients," says CiRA Professor Kenji Osafune, but not all patients will develop ICA. To understand which patients are at risk, the Osafune lab prepared iPS cells from skin cells of several ADPKD patients, some with ICA and others without, to search for molecular markers indicating higher risk. The iPS cells were then differentiated into different cell types of the vasculature and observed.

"We searched for genes that had different expression levels in the two groups," said Osafune. "And we found MMP1." The team then retroactively looked at the expression levels of MMP1 in hundreds of ADPKD patients, and after some statistical analysis found that MMP1 expression could indeed be used as a risk factor for ICA complication.

While ADPKD is a familial disease, not all patients sharing the same mutation have the same risk for ICA. To Osafune, this might indicate other genes could also contribute to the ICA in ADPKD. "We are investigating other markers for ICA using our model," he said.

Paper Details

Journal: Scientific Reports

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

Authors: Tomognaga Ameku 1, Daisuke Taura 2, Masakatsu Sone 2, Tomohiro Numata 3,4, Masahiro Nakamura 1, Fumihiko Shiota 1,5, Taro Toyoda 1, Satoshi Matsui 1, Toshikazu Araoka 1, Tetsuhiko Yasuno 1, Shin-Ichi Mae 1, Hatasu Kobayashi 6, Naoya Kondo 7, Fumiyo Kitaoka 1, Naoki Amano 1, Sayaka Arai 1, Tomoko Ichisaka 1, Norio Matsuura 6, Sumiko Inoue 6, Takuya Yamamoto 1,8, Kazutoshi Takahashi 1, Isao Asaka 1, Yasuhiro Yamada 1,8, Yoshifumi Ubara 9, Eri Muso 7, Atsushi Fukutatsu 5, Akira Watanabe 1,8, Yasunori Sato 10, tatsutoshi Nakahata 1, Yasuo Mori 3,4, Akio Koizumi 6, Kazuwa Nakao 2, Shinya Yamanaka 1 and Kenji Osafune 1

Author Affiliations:

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