Renal Tubule–Specific Angiotensinogen Deletion Attenuates SGLT2 Expression and Ameliorates Diabetic Kidney Disease in Murine Models of Type 1 Diabetes
Bibliographic record
Abstract
The role of the intrarenal renin-angiotensin system (iRAS) in diabetic kidney disease (DKD) progression remains unclear. In this study, we generated mice with renal tubule (RT)-specific deletion of angiotensinogen (Agt; RT-Agt−/−) in both Akita and a streptozotocin (STZ)-induced mouse model of diabetes. Both Akita RT-Agt−/− and STZ-RT-Agt−/− mice exhibited significant attenuation of glomerular hyperfiltration, urinary albumin–to–creatinine ratio, glomerulomegaly, and tubular injury. Urinary Agt, angiotensin II (Ang II), and oxidative stress were decreased in Akita RT-Agt−/− mice compared with Akita mice. Moreover, thickened glomerular basement membranes, podocyte foot process effacement, and podocyte loss were ameliorated in Akita RT-Agt−/− mice compared with Akita mice. Mechanistically, intravital microscopy revealed that attenuation of glomerular hyperfiltration in Akita RT-Agt−/− mice was mediated via efferent arteriole vasodilation and afferent arteriole (AA) vasoconstriction. The AA vasoconstriction was regulated, at least partially, through tubuloglomerular feedback by downregulation of sodium–glucose cotransporter 2 (SGLT2) expression in renal proximal tubules. The renal protective effect of iRAS inactivation in Akita RT-Agt−/− mice was more evident than in Akita mice treated with RAS blockers. In vitro, Ang II stimulated and losartan and apocynin inhibited SGLT2 expression in immortalized human renal proximal tubular cells. These findings suggest targeting the iRAS may constitute effective treatment of DKD. Article Highlights Renin-angiotensin system (RAS) activation plays an important role in the progression of diabetic kidney disease (DKD). However, systemic RAS blockade alone is insufficient to reverse DKD progression. We hypothesized that intrarenal renin-angiotensin system (iRAS) activation plays a crucial role in the progression of DKD. We sought to elucidate the role of the iRAS in DKD progression. Selective deletion of angiotensinogen in renal tubules ameliorated the pathological features of DKD. Our study indicates that iRAS inactivation may be a potential approach for preventing DKD disease severity and its progression.
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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) | 0.001 | 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 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".