Deletion of Angiotensinogen in Renal Tubule Attenuates Diabetic Kidney Disease Progression in Diabetic Mice
Bibliographic record
Abstract
Background: We previously reported that mice overexpressing angiotensinogen (AGT) in renal proximal tubular cells (RPTCs) developed hypertension and kidney injury Kidney Int. 2006). AGT is highly expressed in renal tubules (RTs) in mice and patients with diabetic kidney disease (DKD). We investigated whether genetic deletion of Agt only in renal tubules (RT) could attenuate DKD progression in type 1 diabetic Akita mice. Methods: Male Akita mice with RT-specific Agt knockout (Akita RT-Agt KO) at 20 weeks of age were studied +/- selective A1 adenosine receptor inhibitor (A1aRi), which counteracts the effect of RT-Agt KO. Male Akita controls were also studied. We examined immunohistochemistry in kidney sections, electron microscopy to assess glomerulus basement membrane (GBM) thickness and podocyte foot process effacement, intra-vital confocal microscopy to determine the diameter of glomerular afferent and efferent arterioles, and Western blot and real-time qPCR of protein and gene expression in isolated renal proximal tubules (RPTs). HK2 (human immortalized RPTC cell line) cells were also studied. Results: Akita RT-Agt KO mice had slightly lower systolic blood pressure and fasting blood glucose levels than Akita mice. Akita RT-Agt KO mice displayed significantly attenuated oxidative stress, decreased glomerular hyperfiltration, and decreased glomerulomegaly, tubular injury score, podocyte loss, GBM thickness and podocyte foot process effacement. These findings were associated with decreased urinary albumin/creatinine ratio (UACR), urinary AGT and Ang II levels and SGLT2 expression in RPTs. Intra-vital microscopy revealed decreased afferent arteriole (AA) diameter and increased efferent arteriole (EA) diameter in Akita RT-Agt KO mice cf. Akita mice.Treatment of Akita RT-Agt KO mice with A1aRi increased glomerular filtration rate. In cultured HK2 cells, Ang II stimulated SGLT2 expression, which was attenuated by losartan, NADPH oxidase inhibitors and antioxidants. Conclusion: RT-specific Agt deletion mitigated DKD progression in Akita mice by reducing glomerular hyperfiltration and UACR, decreasing AA and increasing EA diameter, and decreasing podocyte loss, GBM thickness, podocyte foot process effacement and SGLT2 expression in RTs. Funding: Government Support – Non-U.S.
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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) | 0.003 | 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".