Podocytes Soften in Proteinuric CKD: A Potential New Mechanism for Proteinuria?
Bibliographic record
Abstract
Background: Proteinuria is one of the most common manifestations of glomerular injury, and an important predictor of disease progression. Podocytes are a critical component of the glomerular filtration barrier, and as such podocyte injury is a major cause of proteinuria. Historically, investigators have focused on biochemical changes in podocytes that occur following podocyte injury. In contrast, little is known about the changes in the biophysical properties of these highly specialized epithelial cells. Methods: 3 different models of proteinuric glomerular disease were studied: (1) Akita+/- Ren+/- mice (a murine model of diabetes and renin-mediated hypertension that we have recently shown develops progressive glomerulosclerosis that mimics human diabetic kidney disease, n = 7), (2) Myo1e-/- mice (a mouse model of genetic FSGS characterized by deficiency of a non-muscle myosin involved in actomyosin contraction, n = 6), and (3) Col4a5-/- mice, a mouse model of Alport's syndrome (n = 12). The stiffness of glomeruli, glomerular basement membrane (GBM), and podocytes was measured using atomic force microscopy (AFM) and associated histology (picrosirius red, silver, and WT1 staining). Similar stiffness measurements were performed in human FSGS and healthy kidney donor biopsies. Results: AFM measurements revealed that glomerular stiffness increased in Akita+/- Ren+/- and Col4a5-/- mice, a finding that correlated with the degree of glomerulosclerosis. Glomerular stiffness was not increased in Myo1e-/- mice. GBM stiffness was increased in Akita+/- Ren+/- and Myo1e-/- mice, but not in Col4a5-/- Alport's mice. In all 3 mouse models, as well as in human FSGS biopsies, podocytes were softer than in healthy control kidneys. Conclusions: Taken together, these are the first data demonstrating that podocytes soften in proteinuric glomerular disease. Given the major rearrangements in the actomyosin network that occur in podocytes of proteinuric kidneys, our data suggest that podocyte softening may be a common manifestation of podocyte injury. Further work is ongoing to understand whether this softening is solely a consequence of podocyte injury, or if it also contributes to ongoing podocyte damage.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".