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Navarro-Betancourt JR, Papillon J, Guillemette J, et al. Role of IRE1α in podocyte proteostasis and mitochondrial health. Cell Death Discov. 2020;6(1):128doi: 10.1038/s41420-020-00361-4.
Navarro-Betancourt, J. R., Papillon, J., Guillemette, J., Iwawaki, T., Chung, C. F., & Cybulsky, A. V. (2020). Role of IRE1α in podocyte proteostasis and mitochondrial health. Cell death discovery, 6(1), 128. https://doi.org/10.1038/s41420-020-00361-4
Navarro-Betancourt, José R, et al. "Role of IRE1α in podocyte proteostasis and mitochondrial health." Cell death discovery vol. 6,1 (2020): 128. doi: https://doi.org/10.1038/s41420-020-00361-4
Navarro-Betancourt JR, Papillon J, Guillemette J, Iwawaki T, Chung CF, Cybulsky AV. Role of IRE1α in podocyte proteostasis and mitochondrial health. Cell Death Discov. 2020 Nov 19;6(1):128. doi: 10.1038/s41420-020-00361-4. PMID: 33298866; PMCID: PMC7677398.
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Cell Death Discov. 2020 Nov 19;6(1):128. doi: 10.1038/s41420-020-00361-4.

Role of IRE1α in podocyte proteostasis and mitochondrial health.

Cell death discovery

José R Navarro-Betancourt, Joan Papillon, Julie Guillemette, Takao Iwawaki, Chen-Fang Chung, Andrey V Cybulsky

Affiliations

  1. Department of Medicine, McGill University Health Centre Research Institute, McGill University, Montreal, QC, Canada.
  2. Department of Life Science, Kanazawa Medical University, Uchinada, Japan.
  3. Department of Medicine, McGill University Health Centre Research Institute, McGill University, Montreal, QC, Canada. [email protected].

PMID: 33298866 PMCID: PMC7677398 DOI: 10.1038/s41420-020-00361-4

Abstract

Glomerular epithelial cell (GEC)/podocyte proteostasis is dysregulated in glomerular diseases. The unfolded protein response (UPR) is an adaptive pathway in the endoplasmic reticulum (ER) that upregulates proteostasis resources. This study characterizes mechanisms by which inositol requiring enzyme-1α (IRE1α), a UPR transducer, regulates proteostasis in GECs. Mice with podocyte-specific deletion of IRE1α (IRE1α KO) were produced and nephrosis was induced with adriamycin. Compared with control, IRE1α KO mice had greater albuminuria. Adriamycin increased glomerular ER chaperones in control mice, but this upregulation was impaired in IRE1α KO mice. Likewise, autophagy was blunted in adriamycin-treated IRE1α KO animals, evidenced by reduced LC3-II and increased p62. Mitochondrial ultrastructure was markedly disrupted in podocytes of adriamycin-treated IRE1α KO mice. To pursue mechanistic studies, GECs were cultured from glomeruli of IRE1α flox/flox mice and IRE1α was deleted by Cre-lox recombination. In GECs incubated with tunicamycin, deletion of IRE1α attenuated upregulation of ER chaperones, LC3 lipidation, and LC3 transcription, compared with control GECs. Deletion of IRE1α decreased maximal and ATP-linked oxygen consumption, as well as mitochondrial membrane potential. In summary, stress-induced chaperone production, autophagy, and mitochondrial health are compromised by deletion of IRE1α. The IRE1α pathway is cytoprotective in glomerular disease associated with podocyte injury and ER stress.

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