Renal Tubule-Specific Angiotensinogen Knockout Ameliorates Diabetic Kidney Disease in Type 1 Diabetic Akita Mice
Bibliographic record
Abstract
Background: Angiotensinogen (AGT), the sole precursor of angiotensins in the renin-angiotensin system (RAS), is highly expressed in the renal proximal tubules (RPTs) of mice and patients with diabetic kidney disease (DKD). We reported previously that mice specifically overexpressing Agt in RPTs (Agt-Tg) develop hypertension and kidney injury. However, the pathophysiological roles of the intrarenal RAS in DKD progression is not well-defined. We investigated whether genetic deletion of Agt specifically in renal tubules (RT) could improve kidney injury in type 1 diabetic Akita mice. Methods: We generated Akita mice with RT-specific Agt knockout (Akita AgtRT KO) by crossbreeding Akita Agtlox/lox mice with AgtRT KO (tubule-specific Pax8-Cre) mice. Male Akita AgtRT KO, Akita Agtlox/lox, non-diabetic Agtlox/lox and AgtRT KO mice were studied at 20 weeks of age. Physiological data, kidney function, and urinary angiotensin II (Ang II) were assessed. Immunostaining on kidney sections, western blotting (WB) and real-time quantitative PCR (RT-qPCR) were performed to assess protein and gene expression in isolated RPTs. Results: Agt deletion in RT did not significantly affect systolic blood pressure in Akita mice. Fasting blood glucose levels were lower in Akita AgtRT KO vs. Akita mice. Glomerular filtration rate was increased in Akita mice, but was normalized in Akita AgtRT KO mice. The urinary albumin-creatinine ratio (ACR) and Ang II levels were increased in Akita mice, but significantly decreased in Akita AgtRT KO mice. Akita mice exhibited glomerular and tubular hypertrophy, tubular luminal dilation, and necrosis; these abnormalities were markedly attenuated in Akita AgtRT KO mice. Podocyte number (defined by P57 and WT1 staining) was decreased in Akita mice, but was partially restored in Akita AgtRT KO mice. Sodium-glucose cotransporter 2 (SGLT2) expression was lower in Akita AgtRT KO mice than in Akita mice. Urinary glucose excretion was higher in Akita AgtRT KO mice than in Akita mice. Conclusions: Deletion of Agt in RT decreased hyperglycemia, glomerular hyperfiltration, ACR, kidney injury, and SGLT2 expression in Akita mice, demonstrating that inactivation of the intrarenal RAS attenuates DKD progression, at least in part, via down-regulation of SGLT2 expression. 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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 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".