Canagliflozin Inhibits Hedgehog Interacting Protein (Hhip)-Mediated Renal Tubular Cell Senescence in Type 1 Akita Mice
Bibliographic record
Abstract
Background: We have recently reported that hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence-associated secretory phenotype (SASP) in murine diabetic kidney disease (DKD) (Diabetiologia 2023). However, the underlying mechanism(s) are poorly understood. Here, we aimed to elucidate the functional impact of the SGLT2 inhibitor, Canagliflozin (Cana) on tubular Hhip-mediated cell senescence in vivo and in vitro. Methods: Akita renal proximal tubular cells (RPTC)-specific Hhip transgenic (Tg) mice (Akita/Hhip-Tg), Akita/non-Tg and their respective controls (Hhip-Tg or non-Tg) were studied. Cana was administered to Akita mice (Akia/Hhip-Tg vs. Akia/non-Tg) in water (10 or 30 mg/kg/day) from 6 to 20 weeks of age. Primary RPTCs and rat immortalized RPTC cells (IRPTCs) were also employed. Results: Hhip-Tg mice were fertile and phenotypically normal cf. non-Tg. Compared to respective controls at 20-weeks, both Akita/Hhip-Tg and Akita/non-Tg mice displayed typical DKD dysfunction (hypertension, hyperglycemia, polyuria, increased urinary albumin/creatinine ratio and glomerular filtration rate) and dysmorphology (renal hypertrophy, glomerulosclerosis and tubulopathy). These features were more pronounced in Akia/Hhip-Tg than in Akita/non-Tg. Cana administration ameliorated DKD features in a dose-dependent manner. There was evidence of renal tubular SASP—Heightened β-galactosidase activity was seen in Hhip-Tg cf. non-Tg mice, and its activity was more pronounced in Akita/Hhip-Tg cf. Akita/non-Tg mice. In contrast, Cana more effectively inhibited tubular SASP in kidneys of Akita/non-Tg cf. Akita/Hhip-Tg mice. In IRPTCs, excessive Hhip gene expression through either engineered overexpression or high glucose (25mM D-glucose) stimulation promoted extracellular vehicle (apoptotic bodies and microvesicles)-mediated cellular senescence, and their effects were inhibited by the addition of canagliflozin (500nM). Conclusions: Canagliflozin appears to be capable of offsetting DKD-related tubulopathy and tubular senescence, possibly, via the inhibition of excessive Hhip delivered extracellularly in DKD. 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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".