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Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis

Author

Listed:
  • Yujie Zhu

    (Nanjing University School of Life Sciences)

  • Mingchao Zhang

    (Nanjing University School of Life Sciences
    Nanjing University School of Medicine)

  • Weiran Wang

    (Nanjing University School of Life Sciences)

  • Shuang Qu

    (China Pharmaceutical University)

  • Minghui Liu

    (China Pharmaceutical University)

  • Weiwei Rong

    (Nanjing University School of Life Sciences)

  • Wenwen Yang

    (Nanjing University School of Life Sciences)

  • Hongwei Liang

    (China Pharmaceutical University)

  • Caihong Zeng

    (Nanjing University School of Medicine)

  • Xiaodong Zhu

    (Nanjing University School of Medicine)

  • Limin Li

    (China Pharmaceutical University)

  • Zhihong Liu

    (Nanjing University School of Medicine)

  • Ke Zen

    (Nanjing University School of Life Sciences
    China Pharmaceutical University)

Abstract

Renal tubular atrophy is a hallmark of chronic kidney disease. The cause of tubular atrophy, however, remains elusive. Here we report that reduction of renal tubular cell polynucleotide phosphorylase (PNPT1) causes renal tubular translation arrest and atrophy. Analysis of tubular atrophic tissues from renal dysfunction patients and male mice with ischemia-reperfusion injuries (IRI) or unilateral ureteral obstruction (UUO) treatment shows that renal tubular PNPT1 is markedly downregulated under atrophic conditions. PNPT1 reduction leads to leakage of mitochondrial double-stranded RNA (mt-dsRNA) into the cytoplasm where it activates protein kinase R (PKR), followed by phosphorylation of eukaryotic initiation factor 2α (eIF2α) and protein translational termination. Increasing renal PNPT1 expression or inhibiting PKR activity largely rescues IRI- or UUO-induced mouse renal tubular injury. Moreover, tubular-specific PNPT1-knockout mice display Fanconi syndrome-like phenotypes with impaired reabsorption and significant renal tubular injury. Our results reveal that PNPT1 protects renal tubules by blocking the mt-dsRNA-PKR-eIF2α axis.

Suggested Citation

  • Yujie Zhu & Mingchao Zhang & Weiran Wang & Shuang Qu & Minghui Liu & Weiwei Rong & Wenwen Yang & Hongwei Liang & Caihong Zeng & Xiaodong Zhu & Limin Li & Zhihong Liu & Ke Zen, 2023. "Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36664-0
    DOI: 10.1038/s41467-023-36664-0
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    References listed on IDEAS

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    1. Michael Schoof & Lan Wang & J. Zachery Cogan & Rosalie E. Lawrence & Morgane Boone & Jennifer Deborah Wuerth & Adam Frost & Peter Walter, 2021. "Viral evasion of the integrated stress response through antagonism of eIF2-P binding to eIF2B," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Nina A. Bonekamp & Bradley Peter & Hauke S. Hillen & Andrea Felser & Tim Bergbrede & Axel Choidas & Moritz Horn & Anke Unger & Raffaella Lucrezia & Ilian Atanassov & Xinping Li & Uwe Koch & Sascha Men, 2020. "Small-molecule inhibitors of human mitochondrial DNA transcription," Nature, Nature, vol. 588(7839), pages 712-716, December.
    3. Ashish Dhir & Somdutta Dhir & Lukasz S. Borowski & Laura Jimenez & Michael Teitell & Agnès Rötig & Yanick J. Crow & Gillian I. Rice & Darragh Duffy & Christelle Tamby & Takayuki Nojima & Arnold Munnic, 2018. "Mitochondrial double-stranded RNA triggers antiviral signalling in humans," Nature, Nature, vol. 560(7717), pages 238-242, August.
    4. Cedric Darini & Nour Ghaddar & Catherine Chabot & Gloria Assaker & Siham Sabri & Shuo Wang & Jothilatha Krishnamoorthy & Marguerite Buchanan & Adriana Aguilar-Mahecha & Bassam Abdulkarim & Jean Desche, 2019. "An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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