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The p21 dependent G2 arrest of the cell cycle in epithelial tubular cells links to the early stage of renal fibrosis

View ORCID ProfileTakayuki Koyano, Masumi Namba, Tomoe Kobayashi, Kyomi Nakakuni, Daisuke Nakano, Masaki Fukushima, Akira Nishiyama, Makoto Matsuyama
doi: https://doi.org/10.1101/560078
Takayuki Koyano
Division of Molecular Genetics, Shigei Medical Research Institute;
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  • For correspondence: koyano@shigei.or.jp
Masumi Namba
Division of Molecular Genetics, Shigei Medical Research Institute;
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Tomoe Kobayashi
Division of Molecular Genetics, Shigei Medical Research Institute;
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Kyomi Nakakuni
Shigei Medical Research Hospital;
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Daisuke Nakano
Depertment of Pharmacology, Kagawa University Medical School
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Masaki Fukushima
Shigei Medical Research Hospital;
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Akira Nishiyama
Depertment of Pharmacology, Kagawa University Medical School
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Makoto Matsuyama
Division of Molecular Genetics, Shigei Medical Research Institute;
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  • For correspondence: matsuyama@shigei.or.jp
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Abstract

Renal fibrosis is accompanied with the progression of chronic kidney disease (CKD). Despite a number of past and ongoing studies, our understanding of the underlying mechanisms remains elusive. Here we explored the progression of renal fibrosis by using a mouse model, unilateral ureter obstruction (UUO). We found that in the initial stage of the progression where extracellular matrix did not deposit yet, the proximal tubular cells arrested at the G2 of the cell cycle. This G2 arrest was induced prior to activation of both DNA damage checkpoint and Wnt/β-Catenin pathway. Further analyses in vivo and in vitro indicated the cyclin dependent kinase inhibitor p21 is involved in the G2 arrest after the damage. The newly produced monoclonal antibody against p21 revealed that the p21 levels were sharply upregulated in response to the damage during the initial stage, but dropped down toward the later stage. To examine the function of p21 in the progression of renal fibrosis, we constructed the novel p21 deficient mice by i-GONAD. Compared with wild-type mice, p21 deficient mice showed the exacerbation of the fibrosis. Thus we propose that during the initial stage of the fibrosis following the renal damage, tubular cells arrest in the G2 phase depending on p21, thereby safeguarding the kidney functions.

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Posted February 26, 2019.
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The p21 dependent G2 arrest of the cell cycle in epithelial tubular cells links to the early stage of renal fibrosis
Takayuki Koyano, Masumi Namba, Tomoe Kobayashi, Kyomi Nakakuni, Daisuke Nakano, Masaki Fukushima, Akira Nishiyama, Makoto Matsuyama
bioRxiv 560078; doi: https://doi.org/10.1101/560078
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The p21 dependent G2 arrest of the cell cycle in epithelial tubular cells links to the early stage of renal fibrosis
Takayuki Koyano, Masumi Namba, Tomoe Kobayashi, Kyomi Nakakuni, Daisuke Nakano, Masaki Fukushima, Akira Nishiyama, Makoto Matsuyama
bioRxiv 560078; doi: https://doi.org/10.1101/560078

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