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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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    1. Vanessa López-Polo & Mate Maus & Emmanouil Zacharioudakis & Miguel Lafarga & Camille Stephan-Otto Attolini & Francisco D. M. Marques & Marta Kovatcheva & Evripidis Gavathiotis & Manuel Serrano, 2024. "Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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