Recombinant Slit2 Attenuates Renal Fibrosis in a Mouse Model of Diabetic Nephropathy
Bibliographic record
Abstract
Background: We recently described Akita+/- Ren+/- mice as a model that replicates many features of human diabetic nephropathy (DN), including hyperglycemia, hypertension, albuminuria, reduced glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Previously, we showed that recombinant N terminal Slit2 (Slit2) inhibited renal fibrosis in mouse models of postischemic renal fibrosis and obstructive uropathy. To date, however, the anti-fibrotic effects of Slit2 have not been tested in a model of DN. Here we examine the effects of Slit2 therapy in the Akita+/- Ren+/- mouse. Methods: At 6 weeks of age, Akita+/- Ren+/- and Akita-/- Ren-/- mice were randomized to receive thrice weekly intraperitoneal injections of Slit2 (2 ug) or saline, and followed for a further 20 weeks. Results: When compared with saline-treated Akita+/- Ren+/-mice, Slit2-treated Akita+/- Ren+/- mice demonstrated improved survival (66.67% vs. 50%) and decreased systolic blood pressure (142±6.1mmHg vs.167±8.5 mmHg). Structurally, Slit2-treated Akita+/- Ren+/- mice displayed decreased glomerulosclerosis (glomerular picrosirius red score: 0.22±0.02 vs. 0.28±0.02) and interstitial fibrosis (picrosirius red staining: 0.08±0.01 vs. 0.10±0.01, a-smooth muscle actin (aSMA) staining: 0.02±0.00 vs. 0.05±0.01, and vimentin staining: 0.11±0.01 vs. 0.15±0.01). Slit2 treatment attenuated the nuclear translocation of the pro-fibrotic proteins YAP (26.44±7.87% vs 66.20±7.63%) and TAZ (28.55±2.99% vs. 71.42±7.90%, a marker of YAP/TAZ activation) in aSMA positive fibroblasts in mouse kidneys. In vitro, Slit2 decreased TGF-b-induced YAP and TAZ activation in cultured NRK49F fibroblasts, as evidenced by a reduction in YAP (55.55±4.67% vs 92.54±1.36%) and TAZ (30.85±7.877.319 % vs 80.2±3.44%) nuclear localization. All p values < 0.05. Conclusions: Taken together, our results show that Slit2 attenuates diabetic kidney fibrosis, possibly through inhibition of fibroblast YAP and TAZ activity.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".