Monkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease

Tomoyuki Tsukiyama (), Kenichi Kobayashi, Masataka Nakaya, Chizuru Iwatani, Yasunari Seita, Hideaki Tsuchiya, Jun Matsushita, Kahoru Kitajima, Ikuo Kawamoto, Takahiro Nakagawa, Koji Fukuda, Teppei Iwakiri, Hiroyuki Izumi, Iori Itagaki, Shinji Kume, Hiroshi Maegawa, Ryuichi Nishinakamura, Saori Nishio, Shinichiro Nakamura, Akihiro Kawauchi and Masatsugu Ema ()
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Tomoyuki Tsukiyama: Shiga University of Medical Science
Kenichi Kobayashi: Shiga University of Medical Science
Masataka Nakaya: Shiga University of Medical Science
Chizuru Iwatani: Shiga University of Medical Science
Yasunari Seita: Shiga University of Medical Science
Hideaki Tsuchiya: Shiga University of Medical Science
Jun Matsushita: Shiga University of Medical Science
Kahoru Kitajima: Shiga University of Medical Science
Ikuo Kawamoto: Shiga University of Medical Science
Takahiro Nakagawa: Shiga University of Medical Science
Koji Fukuda: Shin Nippon Biomedical Laboratories, Ltd
Teppei Iwakiri: Shin Nippon Biomedical Laboratories, Ltd
Hiroyuki Izumi: Shin Nippon Biomedical Laboratories, Ltd
Iori Itagaki: Shiga University of Medical Science
Shinji Kume: Shiga University of Medical Science
Hiroshi Maegawa: Shiga University of Medical Science
Ryuichi Nishinakamura: Kumamoto University
Saori Nishio: Hokkaido University Graduate School of Medicine
Shinichiro Nakamura: Shiga University of Medical Science
Akihiro Kawauchi: Shiga University of Medical Science
Masatsugu Ema: Shiga University of Medical Science

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Autosomal dominant polycystic kidney disease (ADPKD) caused by PKD1 mutations is one of the most common hereditary disorders. However, the key pathological processes underlying cyst development and exacerbation in pre-symptomatic stages remain unknown, because rodent models do not recapitulate critical disease phenotypes, including disease onset in heterozygotes. Here, using CRISPR/Cas9, we generate ADPKD models with PKD1 mutations in cynomolgus monkeys. As in humans and mice, near-complete PKD1 depletion induces severe cyst formation mainly in collecting ducts. Importantly, unlike in mice, PKD1 heterozygote monkeys exhibit cyst formation perinatally in distal tubules, possibly reflecting the initial pathology in humans. Many monkeys in these models survive after cyst formation, and cysts progress with age. Furthermore, we succeed in generating selective heterozygous mutations using allele-specific targeting. We propose that our models elucidate the onset and progression of ADPKD, which will serve as a critical basis for establishing new therapeutic strategies, including drug treatments.

Date: 2019
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DOI: 10.1038/s41467-019-13398-6

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