Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activates Hedgehog Interacting Protein (Hhip)-Mediated Renal Tubular Cell Senescence in Diabetic Akita Mice
Bibliographic record
Abstract
Background: We recently reported that hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence in murine diabetic kidney disease (DKD) (Diabetologia 2023). However, the underlying mechanism(s) are poorly understood. Nuclear factor erythroid 2–related factor 2 (Nrf2) plays a key role in Sglt2 inhibition-reduced tubular cell senescence in DKD (PMID: 34318973); here, we aimed to elucidate the underlying mechanism of Hhip and Nrf2 interaction on tubular senescence in DKD in vivo and in vitro. Methods: Male Akita, Akita/Nrf2–/– and Akita/Nrf2–/– mice with renal proximal tubular cell (RPTC)-specific Nrf2 transgene (Akita/Nrf2–/–/Nrf2RPTC-Tg), and their respective control mice (non-Akita or Nrf2–/–) were studied. Primary RPTCs and human immortalized HK-2 cells were the in vitro model used. Results: Compared to respective controls at the age of 20 weeks, Akita mice displayed typical DKD characteristics (increased urinary albumin/creatinine ratio and glomerular filtration rate) and renal dysmorphology (renal hypertrophy, glomerulosclerosis and tubulopathy); those changes were attenuated in Akita/Nrf2–/– mice. As compared with Akita, Akita/Nrf2–/– mice had less renal tubular Hhip gene expression and decreased tubular senescence as assessed by β-galactosidase activity and p16-, p21-, and p53- immunostaining. However, these protective features were markedly lost in Akita/Nrf2–/–/Nrf2RPTC-Tg kidneys. In vitro, Nrf2 activators (oltipraz or CDDO-Me) significantly stimulated Hhip gene expression (promotor activity, Hhip mRNA and protein expression), while also promoted cellular senescence. Those effects were more pronounced under high glucose milieu. In contrast, HK-2 cells with Nrf2 knockout largely prevented the above phenotypes. Conclusion: Nrf2 activates Hhip gene expression in RPTCs. In diabetes, activation of both Nrf2 and Hhip works in concert to accelerate tubular senescence 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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".