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Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury

Nature Medicine volume 16, pages 535–543 (2010)Cite this article

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Abstract

Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH2-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.

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Figure 1: Clinical-pathological features of AKI models.
Figure 2: Repair of renal tubular cells in models of AKI.
Figure 3: Profibrogenic factor production in G2/M-arrested proximal tubular cells in vitro and in AKI models in vivo.
Figure 4: Reversal of G2/M arrest rescues the fibrogenic effect in aristolochic acid-treated HK-2 cells and in the UIRI mouse model.
Figure 5: Prolonged G2/M arrest, induced by alternative strategies, causes a profibrotic phenotype both in vitro and in vivo.
Figure 6: JNK signaling activation mediates G2/M arrest–induced profibrogenic cytokines upregulation.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants DK39773 and DK72381 to J.V.B. and DK074030 to J.V.S. L.Y. was supported by a fellowship from the International Society of Nephrology.

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Li Yang, Tatiana Y Besschetnova, Craig R Brooks, Jagesh V Shah & Joseph V Bonventre

  2. Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China

    Li Yang

  3. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    Tatiana Y Besschetnova & Jagesh V Shah

  4. Division of Health Sciences and Technology, Harvard–Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Jagesh V Shah & Joseph V Bonventre

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  1. Li Yang
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Contributions

L.Y. and J.V.B. designed the experiments and wrote the manuscript. L.Y. performed experiments and collected and analyzed data. J.V.B. supervised the project. J.V.S. designed the in vitro rescue experiment and advised on cell biology. T.Y.B. helped collect data and edited the manuscript. C.R.B. helped with making lentivirus shRNA specific for ATM. All authors discussed the results and implications and commented on the manuscript.

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Correspondence to Joseph V Bonventre.

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Yang, L., Besschetnova, T., Brooks, C. et al. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16, 535–543 (2010). https://doi.org/10.1038/nm.2144

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