Deletion of IRE1α Exacerbates Diabetic Nephropathy in Mice
Bibliographic record
Abstract
Background: Protein misfolding in the endoplasmic reticulum (ER) of podocytes is an important contributor to the pathogenesis of glomerular diseases. ER protein misfolding activates a compensatory signaling network called the unfolded protein response (UPR). Deletion of the UPR transducer, inositol-requiring enzyme 1α (IRE1α) in mouse podocytes leads to podocyte injury and albuminuria in aging, and exacerbates injury in glomerulonephritis. This study addresses the role of the UPR and IRE1α in diabetic nephropathy. Methods: We studied mice with podocyte-specific deletion/knockout (KO) of IRE1α. Hyperglycemia was induced in male mice (age 3-4 months) with streptozotocin. Results: Streptozotocin-treated control and IRE1α KO mice developed comparable hyperglycemia (diabetes). Diabetes caused progressive albuminuria in control mice (3.7 mg/mg creatinine at 6 months) that was exacerbated in IRE1α KO mice (8.5 mg/mg creatinine; P<0.01). Albuminuria was ˜1 mg/mg creatinine in non-diabetic groups (4-13 mice/group). Compared to diabetic controls, diabetic IRE1α KO mice showed a reduction in podocytes (WT1-positive cells; P<0.0001) and synaptopodin (P<0.05). Both non-diabetic and diabetic IRE1α KO mice showed increased glomerular matrix expansion compared to their respective controls. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; changes included widening of foot processes and glomerular basement membrane, microvesiculation of podocyte plasma membranes, and markedly dilated ER and mitochondrial architectural damage in podocytes. Activation of the UPR (increased glomerular ER chaperones) and autophagy (increased LC3-II, decreased p62) was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD (Nephroseq) database demonstrated activation of pathways and gene ontology categories, as well as induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy. Conclusions: Mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy. This was associated with an attenuation of the glomerular UPR and autophagy, implying a protective mechanism mediated via IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways. 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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".