Renal Tubule-Specific Deletion of Angiotensinogen Gene Ameliorates Tubulopathy via Attenuation of Mitochondrial Dysfunction and Senescence in Akita Mouse Kidneys
Bibliographic record
Abstract
Background: We have reported that renal tubule (RT)-specific angiotensinogen (Agt) gene deletion attenuates glomerular hyperfiltration, tubular injury, and urinary albumin-creatinine ratio, and decreases SGLT2 expression in T1D Akita mice (Diabetes 2025). The present study aimed to investigate if RT-deletion of Agt attenuates tubulopathy and explore underlying mechanisms. Methods: We studied male non-diabetic control, RT-Agt knockout (KO), Akita, and Akita RT-Agt KO mice at 20 and 42 weeks. HK-2 (human immortalized proximal tubule cell line) and MDCK (Madin-Darby Canine Kidney) cells were also studied. Renal proximal tubular (RPT) and distal tubular (DT) cell size, luminal area, mitochondrial function, senescence and senescence-associated secretory phenotype (SASP) expression were assessed. Results: RPT and DT cell size, luminal area, oxidative stress (dihydroethidium staining), oxidative DNA damage (8-Hydroxy-2’-deoxyguanosine staining) and disruption of mitochondrial cristae (electronic microscopy) were significantly increased in Akita mice. These abnormalities were markedly attenuated in Akita RT-Agt- KO mice. Akita kidneys also exhibited senescence-associated β-galactosidase (SA β-Gal) activity and SASP (Ccl2, Cxcl1 and Tnf-α) expression. Moreover, immunofluorescent staining of Ang II was increased and colocalized with the DT marker (lycopersicon esculentum lectin) in Akita mice, along with elevated markers of oxidative DNA damage and senescence marker (p16). These changes were significantly attenuated in Akita RT-Agt KO mice. In vitro, culture of HK cells with high glucose (35 mM D-glucose) and Ang II evoked mitochondrial oxidative stress, reduced mitochondrial transmembrane potential (MitoSox and JC1 staining, respectively) and augmented SA β-Gal activity. These changes were attenuated by losartan (an AT1R blocker) or apocynin (an NOX4 inhibitor). Finally, addition of senescent MDCK-derived conditioned medium to HK-2 cells facilitated the epithelial-to-mesenchymal transition in HK2 cells and vice versa, which was reversed by losartan or apocynin treatment. Conclusion: RT-derived Agt/Ang II triggers tubulopathy, at least in part, through ROS-mediated DNA damage, mitochondrial dysfunction and senescence in Akita mice. 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 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| 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".