Abstract 5264: Recombinant Human Angiotensin Converting Enzyme 2 Normalizes Blood Pressure and Reduces the Progression of Diabetic Nephropathy
Bibliographic record
Abstract
Background: Diabetes nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function exacerbates diabetic kidney injury while renal ACE2 is downregulated in diabetic nephropathy. We hypothesize that recombinant human ACE2 (rhACE2) will slow the progression of diabetic kidney injury. Methods and Results: Male 12-week old diabetic Akita mice ( Ins2 WT/C96Y ) and controls ( Ins2 WT/WT ) were injected daily with rhACE2 (2 mg/kg, i.p.) or placebo for four consecutive weeks. In Akita Ins2 WT/C96Y mice injected with hrACE2, plasma ACE2 activity showed a marked increase resulting in significant reduction in urinary albumin excretion (118±21 vs 224±16 μ g/24 hrs; n=6~8; p<0.05). Treatment with rhACE2 decreased renal cortical angiotensin (Ang) II (12.1±1.9 vs 22.4±3.2 pg/mg; p<0.05) and increased Ang (1–7) (14.2±2.1 vs 8.8±1.9 pg/mg; p<0.05) levels, respectively, independent of changes in the expression of Ace and Ace2 while NADPH oxidase activity in renal cortical tissue from Akita mice was reduced by treatment with rhACE2 (364±45 vs 1720±277 RLU/sec/mg protein; n=6, p<0.05). These effects resulted in normalization of the increased extracellular matrix gene expression ( α -smooth muscle actin, collagen III and fibronectin), reduction in glomerular volume and basement membrane thickness in the diabetic Akita mice. Activation of protein kinase C (PKC)á and PKCâ was reduced by 60 –70% in Akita diabetic mice treated with rhACE2. Ang II and high glucose-induced reactive oxygen species generation was evaluated using lucigenin-based NADPH oxidase activity and DHE fluorescence in cultured rat mesangial cells was suppressed by 25 and 250 ng/ml of rhACE2 in a dose-dependent manner. The mild hypertension in Akita Ins2 WT/C96Y mice was normalized by treatment with rhACE2 (122.3±2.1 vs 108.4±1.9 mmHg; n=6, p<0.05) while the beneficial effects seen with rhACE2 occurred in the absence of hyperkalemia or acute renal failure and without a differential impact on hyperglycemia in the Akita diabetic model. Conclusions: We conclude that biologic antagonism of the RAS using rhACE2 can slow the progression of diabetic kidney injury and ACE2 may prove to be a useful adjunctive therapy for diabetic kidney disease.
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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 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".