Podocyte-Specific Deletion of SHP-1 Restored SUMOylation of Podocin and Reversed the Progression of Diabetic Kidney Disease
Bibliographic record
Abstract
Background: Both clinical and experimental data suggest that podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD). Although the mechanisms underlying the development of podocyte loss is not completely understood, critical structure proteins such as podocin have been shown to play a major role in podocyte survival and function. We have reported that SHP-1 (a protein tyrosine phosphatase) expression is increased in podocytes of diabetic mice and glomeruli of patients with diabetes. However, the contribution of SHP-1 in podocytes has not been investigated. Methods: Conditional podocyte specific SHP-1 deficient mice (Podo-SHP-1-/-) have been generated to evaluate the impact of SHP-1 on renal function (albuminuria and GFR) and kidney pathology. Deletion of SHP-1 was performed at 4 weeks of age (prevention group; prior to the onset of diabetes) and after 16 weeks of diabetes (reversibility group). Mice were euthanized at 24 weeks of age for renal function and histology assessment. Results: Elevated albuminuria and GFR seeing in the diabetic mice were preserved in the diabetic mice with specific podocyte ablation of SHP-1 at 4 weeks of age. Interestingly, late deletion of SHP-1 in podocytes after 16 weeks of diabetes also restored renal function and prevented kidney disease progression. Structural changes such as mesangial cell expansion, glomerular hypertrophy, GBM thickening, podocyte foot process effacement and podocyte loss induced by diabetes were also blunted and even reversed with deletion SHP-1 specifically in podocytes. Moreover, podocyte-specific deletion of SHP-1 at 4 weeks and 20 weeks of age prevented diabetes-induced expression of Coll IV, fibronectin, RhoA, and ROCK1, whereas it restored nephrin, podocin and TRPC6 expression. Mass spectrometry analysis revealed that SHP-1 reduced SUMO2 expression and is association with podocin which was also confirmed by immunoprecipitation and co-immunofluorescence in patients with diabetes kidney disease, while podocyte-specific deletion of SHP-1 allow to maintain podocin integrity and stability in a diabetic context. Conclusions: Our data uncovered a new role of SHP-1 in the regulation of cytoskeleton dynamics and slit diaphragm protein expression and stability, and specific deletion of SHP-1 contribute to preserve podocyte function and even reverse DKD progression. Funding: Government Support - Non-U.S.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".