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

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 fr...

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Autores principales: Zhu, Yujie, Zhang, Mingchao, Wang, Weiran, Qu, Shuang, Liu, Minghui, Rong, Weiwei, Yang, Wenwen, Liang, Hongwei, Zeng, Caihong, Zhu, Xiaodong, Li, Limin, Liu, Zhihong, Zen, Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984537/
https://www.ncbi.nlm.nih.gov/pubmed/36869030
http://dx.doi.org/10.1038/s41467-023-36664-0
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author Zhu, Yujie
Zhang, Mingchao
Wang, Weiran
Qu, Shuang
Liu, Minghui
Rong, Weiwei
Yang, Wenwen
Liang, Hongwei
Zeng, Caihong
Zhu, Xiaodong
Li, Limin
Liu, Zhihong
Zen, Ke
author_facet Zhu, Yujie
Zhang, Mingchao
Wang, Weiran
Qu, Shuang
Liu, Minghui
Rong, Weiwei
Yang, Wenwen
Liang, Hongwei
Zeng, Caihong
Zhu, Xiaodong
Li, Limin
Liu, Zhihong
Zen, Ke
author_sort Zhu, Yujie
collection PubMed
description 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.
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spelling pubmed-99845372023-03-05 Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis Zhu, Yujie Zhang, Mingchao Wang, Weiran Qu, Shuang Liu, Minghui Rong, Weiwei Yang, Wenwen Liang, Hongwei Zeng, Caihong Zhu, Xiaodong Li, Limin Liu, Zhihong Zen, Ke Nat Commun Article 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. Nature Publishing Group UK 2023-03-03 /pmc/articles/PMC9984537/ /pubmed/36869030 http://dx.doi.org/10.1038/s41467-023-36664-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhu, Yujie
Zhang, Mingchao
Wang, Weiran
Qu, Shuang
Liu, Minghui
Rong, Weiwei
Yang, Wenwen
Liang, Hongwei
Zeng, Caihong
Zhu, Xiaodong
Li, Limin
Liu, Zhihong
Zen, Ke
Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
title Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
title_full Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
title_fullStr Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
title_full_unstemmed Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
title_short Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
title_sort polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsrna-pkr-eif2α axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984537/
https://www.ncbi.nlm.nih.gov/pubmed/36869030
http://dx.doi.org/10.1038/s41467-023-36664-0
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