Deletion of inositol-requiring enzyme-1α in podocytes disrupts glomerular capillary integrity and autophagy
Bibliographic record
Abstract
Inositol-requiring enzyme-1α (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endoribonuclease kinase that plays an essential function in extraembryonic tissues during normal development and is activated during ER stress. To address the functional role of IRE1α in glomerular podocytes, we produced podocyte-specific IRE1α-deletion mice. In male mice, deletion of IRE1α in podocytes resulted in albuminuria beginning at 5 mo of age and worsening with time. Electron microscopy revealed focal podocyte foot-process effacement in 9-mo-old male IRE1α-deletion mice, as well as microvillous transformation of podocyte plasma membranes. Compared with control, glomerular cross-sectional and capillary lumenal areas were greater in deletion mice, and there was relative podocyte depletion. Levels of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II expression and c-Jun N-terminal kinase-1 phosphorylation were decreased in IRE1α-deletion glomeruli, in keeping with reduced autophagy. Deletion of IRE1α exacerbated glomerular injury in anti-glomerular basement membrane nephritis. In cell culture, IRE1α dominant-negative mutants reduced the physiological (basal) accumulation of LC3B-II and the size of autophagic vacuoles but did not affect ER-associated degradation. Thus IRE1α is essential for maintaining podocyte and glomerular integrity as mice age and in glomerulonephritis. The mechanism is related, at least in part, to the maintenance of autophagy in podocytes.
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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) | 0.001 | 0.000 |
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".