PMID- 33298866
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201213
IS  - 2058-7716 (Print)
IS  - 2058-7716 (Electronic)
IS  - 2058-7716 (Linking)
VI  - 6
IP  - 1
DP  - 2020 Nov 19
TI  - Role of IRE1alpha in podocyte proteostasis and mitochondrial health.
PG  - 128
LID - 10.1038/s41420-020-00361-4 [doi]
LID - 128
AB  - 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-1alpha (IRE1alpha), a 
      UPR transducer, regulates proteostasis in GECs. Mice with podocyte-specific 
      deletion of IRE1alpha (IRE1alpha KO) were produced and nephrosis was induced with 
      adriamycin. Compared with control, IRE1alpha KO mice had greater albuminuria. 
      Adriamycin increased glomerular ER chaperones in control mice, but this 
      upregulation was impaired in IRE1alpha KO mice. Likewise, autophagy was blunted in 
      adriamycin-treated IRE1alpha KO animals, evidenced by reduced LC3-II and increased 
      p62. Mitochondrial ultrastructure was markedly disrupted in podocytes of 
      adriamycin-treated IRE1alpha KO mice. To pursue mechanistic studies, GECs were 
      cultured from glomeruli of IRE1alpha flox/flox mice and IRE1alpha was deleted by Cre-lox 
      recombination. In GECs incubated with tunicamycin, deletion of IRE1alpha attenuated 
      upregulation of ER chaperones, LC3 lipidation, and LC3 transcription, compared 
      with control GECs. Deletion of IRE1alpha 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 IRE1alpha. The IRE1alpha pathway is cytoprotective in 
      glomerular disease associated with podocyte injury and ER stress.
FAU - Navarro-Betancourt, Jose R
AU  - Navarro-Betancourt JR
AD  - Department of Medicine, McGill University Health Centre Research Institute, 
      McGill University, Montreal, QC, Canada.
FAU - Papillon, Joan
AU  - Papillon J
AD  - Department of Medicine, McGill University Health Centre Research Institute, 
      McGill University, Montreal, QC, Canada.
FAU - Guillemette, Julie
AU  - Guillemette J
AD  - Department of Medicine, McGill University Health Centre Research Institute, 
      McGill University, Montreal, QC, Canada.
FAU - Iwawaki, Takao
AU  - Iwawaki T
AD  - Department of Life Science, Kanazawa Medical University, Uchinada, Japan.
FAU - Chung, Chen-Fang
AU  - Chung CF
AD  - Department of Medicine, McGill University Health Centre Research Institute, 
      McGill University, Montreal, QC, Canada.
FAU - Cybulsky, Andrey V
AU  - Cybulsky AV
AUID- ORCID: 0000-0003-4348-2348
AD  - Department of Medicine, McGill University Health Centre Research Institute, 
      McGill University, Montreal, QC, Canada. andrey.cybulsky@mcgill.ca.
LA  - eng
GR  - MOP-133492/Gouvernement du Canada | Canadian Institutes of Health Research 
      (Instituts de Recherche en Sante du Canada)/
GR  - PJ9-166216/Gouvernement du Canada | Canadian Institutes of Health Research 
      (Instituts de Recherche en Sante du Canada)/
GR  - PJ9-169678/Gouvernement du Canada | Canadian Institutes of Health Research 
      (Instituts de Recherche en Sante du Canada)/
PT  - Journal Article
DEP - 20201119
PL  - United States
TA  - Cell Death Discov
JT  - Cell death discovery
JID - 101665035
PMC - PMC7677398
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/12/11 06:00
MHDA- 2020/12/11 06:01
PMCR- 2020/11/19
CRDT- 2020/12/10 05:44
PHST- 2020/08/28 00:00 [received]
PHST- 2020/10/23 00:00 [accepted]
PHST- 2020/10/09 00:00 [revised]
PHST- 2020/12/10 05:44 [entrez]
PHST- 2020/12/11 06:00 [pubmed]
PHST- 2020/12/11 06:01 [medline]
PHST- 2020/11/19 00:00 [pmc-release]
AID - 10.1038/s41420-020-00361-4 [pii]
AID - 361 [pii]
AID - 10.1038/s41420-020-00361-4 [doi]
PST - epublish
SO  - Cell Death Discov. 2020 Nov 19;6(1):128. doi: 10.1038/s41420-020-00361-4.