IRE1α Is Essential for Podocyte Proteostasis and Mitochondrial Health
Bibliographic record
Abstract
Background: 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. Methods: 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. Results: 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 IRE1αKO 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. Conclusions: 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. Funding: Government Support - Non-U.S.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".