FO033PODOCYTE SPECIFIC GLYCOGEN SYNTHASE KINASE 3 IS CRITICAL FOR KIDNEY FUCTION IN DEVELOPMENT AND MATURITY
Bibliographic record
Abstract
Introduction and Aims: Glycogen synthase kinase 3 (GSK3) is a multi-functional serine/threonine kinase existing as two distinct but related isoforms (alpha and beta). There is evidence that the GSK3 isoforms have different functions: GSK3 beta null mice die during late embryogenesis whereas total GSK3 alpha knockout mice are viable and interestingly, exhibit enhanced insulin sensitivity. A number of cell-specific GSK3 knockout mouse models have been described and indicate that the functions of the GSK3 isoforms are cell-type dependent. This study aims to examine the importance of GSK3 in the podocyte. Methods: In order to investigate the role of the GSK3 isoforms in podocyte development, we have used Cre/ LoxP technology to generate mice with podocyte-specific ablation of GSK3 alpha and/or GSK3 beta in development (using the podocin cre driver) and in maturity (using the doxycycline inducible podocin RtTA - tet-o-cre driver). Results: Mice developmentally lacking either GSK3 alpha or GSK3 beta specifically in the podocyte are viable with normal life span (up to 2 years) and normal renal histology. In contrast, mice null for both GSK3 isoforms, although born at normal Mendelian frequency, die predictably at 12-16 days with severe albuminuria. These mice have vacuolated glomeruli and glomerulosclerosis. When GSK3 alpha and beta are knocked out together after full glomerular development, at 4 weeks of age, this also results in significant renal disease which develops within 2-weeks of knockdown. It consists of significant albuminuria and renal failure in some mice. Furthermore, there is evidence of a crescentic proliferative glomerulopathy, together with massive fibrosis and glomerulosclerosis in the mice. Mechanistically the wnt signalling pathway is up-regulated and beta catenin activated throughout the kidney. Interestingly preliminary data suggests that signalling pathways other than the wnt pathway are important in this process as contemporaneous genetic knock down of podocyte beta catenin in the developmental model does not seem to improve survival. These pathways are currently being investigated through a glomerular transcriptomic approach.
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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) | 0.006 | 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".