Deletion of Angiotensinogen in Renal Tubules Attenuates Tubular Senescence in Diabetic Kidney Disease
Bibliographic record
Abstract
Background: We reported previously that renal tubule (RT)-specific angiotensinogen (Agt) deletion attenuates kidney injury in type 1 diabetic Akita mice by reducing glomerular hyperfiltration, tubular injury score, urinary albumin-creatinine ratio and SGLT2 expression in renal proximal tubules (RPTs) (ASN’23, SA-PO423). Angiotensin II (Ang II) elicits reactive oxygen species (ROS), triggering oxidative DNA damage, cellular senescence and senescence-associated secretory phenotype (SASP). This study aimed to investigate whether RT-Agt deletion attenuates kidney injury by mitigating tubular senescence in Akita mice. Methods: Diabetic Akita mice with RT-specific deletion of Agt (Akita RT-Agt KO) were generated by crossbreeding Pax8-Cre mice with Agt-floxed Akita mice. Male non-diabetic control, RT-Agt KO, Akita, and Akita RT-Agt KO mice were studied at 20 weeks of age. In vitro, Madin-Darby Canine Kidney (MDCK, a distal tubule (DT) cell line) cells and HK-2 (human immortalized proximal tubule cell line) cells were used. Results: Akita mice exhibited increased urinary AGT and Ang II, as well as senescence-associated β-galactosidase positive renal tubules vs. control and RT-Agt- KO mice and these were normalized in Akita RT-Agt KO mice. Notably, immunofluorescent staining of Ang II was increased and colocalized with the DT marker (lycopersicon esculentum lectin (LEL)) in Akita mice, along with elevated markers of oxidative DNA damage (8-Hydroxy-2’-deoxyguanosine (8-OHdG)) and senescence marker (p16) staining. These changes were normalized in Akita RT-Agt KO mice. Moreover, SASP components including CCL2, CXCL1, and TNF-α mRNA were upregulated in Akita mouse kidneys and attenuated in Akita RT-Agt KO mice. In vitro, Ang II-induced senescence in MDCK, which was attenuated by losartan (an AT1R blocker) or NAC (N-acetyl L-cysteine, an ROS inhibitor). Finally, addition of senescent MDCK-derived conditioned medium to HK-2 culture facilitated the epithelial-to-mesenchymal transition, which was reversed by losartan or NAC treatment. Conclusion: RT-derived Agt/Ang II triggers cellular senescence in renal tubules via ROS-mediated DNA damage and the p16 pathway, leading to SASP and increased tubular injury in Akita mice. These results highlight the importance of inhibiting intrarenal RAS to prevent DKD progression. 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 | 0.000 | 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".