Canagliflozin Greatly Improves Mitochondrial Stress Response in Proximal Tubular Cells (PTCs) of Mice with Combined Hypertension and Type 1 Diabetes
Bibliographic record
Abstract
Background: Canagliflozin (CANA) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor with blood glucose lowering effects. CANA promotes kidney protection in patients with type 2 diabetes (T2D), as well as cardiovascular complications. Both diabetes and hypertension induce mitochondrial dysfunction and oxidative stress. However, it is still unclear whether CANA modulates mitochondrial function in diabetic kidney diseases. Methods: In vivo: Male and female 8 weeks old genetic hypertensive mice (Lin) were subjected to daily intraperitoneal injections of streptozotocin (STZ) for 5 days. 4 weeks after the STZ injections, mice were fed either regular or CANA-infused diet for 1 week. Urinary albumin levels were determined by ELISA and urinary creatinine by colorimetric assay. Proximal tubular epithelial cells (PTCs) isolated from experimental mice were subjected to Seahorse MitoStress test. Kidney OXPHOS complexes were analyzed by Western blotting. In vitro: PTCs were isolated from Fvb mice, treated with 100nM Ang II + 30mM glucose for 24h, followed by treatment with 10uM CANA or vehicle for 24h. Results: Male and females LinSTZ mice had elevated albumin to creatinine ratio (ACR), while CANA reverted the ACR increase in males (23,578 ± 7,937 vs 3,014 ± 492.5, n=4, P<0.05) and females (6,758 ± 906.8 vs 623.4 ± 103.8, n=3, P<0.01). Overall, PTCs from LinSTZ + CANA greatly improved oxygen consumption rate (OCR) throughout the mitochondrial stress test (P<0.0001), with significant increase in OCR after inhibition of complexes I, II, and V in males (n=4, P<0.05) and females (n=3, P<0.05). A trend to decrease protein levels of OXPHOS complexes were also observed in the kidney of LinSTZ + CANA mice (n=2-3, P>0.08). In vitro, CANA overall effect on OCR was more pronounced in males, whereas in females there was a higher response to the disruption of mitochondrial oxidative phosphorylation by FCCP (P<0.001). Conclusions: Canagliflozin promoted kidney protection, shown by improvement of albuminuria in hypertensive-diabetic mice. Moreover, we show evidence of improved mitochondria function induced by CANA in vivo and in vitro. Besides the benefits related to restoration of glucose homeostasis, CANA could play a role on proximal tubular mitochondrial function and remodeling. Funding: Private Foundation Support
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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".