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Abstract: PO1993

IRE1α Is Essential for Podocyte Proteostasis and Mitochondrial Health

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Navarro-Betancourt, José R., McGill University, Montreal, Quebec, Canada
  • Papillon, Joan, McGill University, Montreal, Quebec, Canada
  • Guillemette, Julie, McGill University, Montreal, Quebec, Canada
  • Iwawaki, Takao, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan
  • Cybulsky, Andrey V., McGill University, Montreal, Quebec, Canada

Glomerular epithelial cell (GEC)/podocyte proteostasis is disrupted in glomerular diseases. To maintain proteostasis, the endoplasmic reticulum (ER) orchestrates the unfolded protein response (UPR), which includes upregulation of chaperones and clearance of misfolded proteins via autophagy. Inositol requiring enzyme-1α (IRE1α) resides in the ER membrane and is a transducer of the UPR. This study characterizes the mechanisms by which IRE1α regulates proteostasis in GECs.


Mice with podocyte-specific deletion of IRE1α (IRE1α KO) were produced by breeding IRE1α flox/flox mice with mice expressing podocin-Cre recombinase. Nephrosis was induced with a single injection of adriamycin (ADR). GECs were cultured from glomeruli of IRE1α flox/flox mice and IRE1α was deleted by transduction of Cre recombinase. Cellular oxygen consumption rate (OCR) was quantified using the Seahorse mitochondrial stress test. Mitochondria were visualized using MitoTracker Red CMXRos or MitoTracker Green FM.


Podocyte-specific IRE1α KO mice had greater ADR-induced albuminuria compared to control littermates. ADR increased expression of ER chaperones in glomeruli of control mice, but this upregulation was impaired in IRE1α KO mice. Autophagy induction was blunted in ADR-treated IRE1α KO animals, evidenced by reduced LC3-II and increased p62 levels, compared to treated controls. Electron microscopy showed prominent swelling of the ER and mitochondrial injury in podocytes of ADR-treated IRE1α KO mice. In cultured GECs incubated with tunicamycin (TM), deletion of IRE1α or chemical inhibition of the IRE1α RNase with 4μ8C attenuated upregulation of ER chaperones and LC3 lipidation compared to control. LC3 transcription and total LC3 protein levels were also reduced in TM-treated IRE1α KO GECs. Compared to control, IRE1α KO GECs showed decreased maximal and ATP-linked OCR. Mitochondrial membrane potential was lower in IRE1α KO GECs than in control, while total mitochondrial mass was similar in both groups. Inhibition of IRE1α signaling increased ER stress-induced apoptosis.


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.


  • Government Support - Non-U.S.