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A circular RNA, circPTPN14, increases MYC transcription by interacting with FUBP1 and exacerbates renal fibrosis

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Abstract

Fibrosis is a relentlessly progressive and irreversible cause of organ damage, as in chronic kidney disease (CKD), but its underlying mechanisms remain elusive. We found that a circular RNA, circPTPN14, is highly expressed in human kidneys with biopsy-proved chronic interstitial fibrosis, mouse kidneys subjected to ischemia/reperfusion (IR) or unilateral ureteral obstruction (UUO), and TGFβ1-stimulated renal tubule epithelial cells (TECs). The intrarenal injection of circPTPN14 shRNA alleviated the progression of fibrosis in kidneys subjected to IR or UUO. Knockdown of circPTPN14 in TECs inhibited TGFβ1-induced expression of profibrotic genes, whereas overexpressing circPTPN14 increased the profibrotic effect of TGFβ1. The profibrotic action of circPTPN14 was ascribed to an increase in MYC transcription. The binding of circPTPN14 to the KH3 and KH4 domains of far upstream element (FUSE) binding protein 1 (FUBP1) enhanced the interaction between FUBP1 and FUSE domain, which was required for the initiation of MYC transcription. In human kidneys (n = 30) with biopsy-proved chronic interstitial fibrosis, the expression of circPTPN14 positively correlated with MYC expression. Taken together these studies show a novel mechanism in the pathogenesis of renal fibrosis, mediated by circPTPN14, which can be a target in the diagnosis and treatment of CKD.

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Acknowledgements

We thank Prof. Pedro A. Jose and Prof. Ines Armando (The George Washington University, USA) for precious suggestions and draft revising. We are grateful for the technical support by the Core Facilities, Zhejiang University School of Medicine, and the Center of Cryo-Electron Microscopy of Zhejiang University.

Funding

This study was supported by the funding from Primary Research and Development Plan of Zhejiang Province (2020C03034) to Fei Han, and National Natural Science Foundation of China (81770674) to Fei Han.

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Author notes

  1. Wanyun Nie, Mobai Li and Boqiang Liu contributed equally to this work.

Authors and Affiliations

  1. Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, 310003, China

    Wanyun Nie, Ying Zhang, Yuxi Wang, Junni Wang, Lini Jin, Anqi Ni, Liang Xiao, Jianghua Chen & Fei Han

  2. Department of Orthopaedic Surgery in Sir Run Run Shaw Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Mobai Li

  3. Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Boqiang Liu

  4. Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Xiao Z. Shen

  5. International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, China

    Weiqiang Lin

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  1. Wanyun Nie
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Contributions

F.H., W.L., W.N., M.L. and B.L. conceived and designed the research. W.N., M.L. and B.L. performed most of the experiments, with the assistance from Y.Z., Y.W., J.W., L.J. and A.N., under the supervision of F.H.. L.X., X.Z.S., J.C. provided administrative support and suggestion. W.N., M.L. and B.L. wrote the original manuscript, with reviewing and editing by F.H.. All authors read and approved this version of manuscript.

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Correspondence to Weiqiang Lin or Fei Han.

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Nie, W., Li, M., Liu, B. et al. A circular RNA, circPTPN14, increases MYC transcription by interacting with FUBP1 and exacerbates renal fibrosis. Cell. Mol. Life Sci. 79, 595 (2022). https://doi.org/10.1007/s00018-022-04603-9

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