miR-486-5p Protects Against Ischemic AKI and Prevents Transition to CKD
Bibliographic record
Abstract
Background: Recovery from acute kidney injury (AKI) is associated with increased risk for progressive chronic kidney disease (CKD). We previously showed that microRNA (miR)-486-5p protects against kidney ischemia-reperfusion (IR) injury in mice, with targeting of phosphatase and tensin homolog (PTEN) and downregulation of proximal tubular genes involved in apoptosis and tumor necrosis factor signaling. In cultured human endothelial cells however, miR-486-5p inhibits endothelial nitric oxide synthase (eNOS) expression. Here, we studied the effects of miR-486-5p on IR AKI and CKD development in rats with a focus on vasculature. Methods: Kidney IR injury was induced in male rats by bilateral renal pedicle clamping followed by reperfusion. Lipid-encapsulated miR-486-5p (0.5mg/kg) was injected i.v. at the start of reperfusion. Outcomes were assessed after 24hr and 10 weeks. Kidney blood flow was measured by laser doppler flowmetry. Endothelium-dependent mesenteric artery reactivity was evaluated by myography. Results: In rats with IR AKI, miR-486-5p preserved regional kidney blood flow at 24hr (p<0.01,n=7) and prevented increases in plasma Cr (p<0.001,n=10), neutrophil and macrophage infiltration, and apoptosis. miR-486-5p had no effect on kidney PTEN expression, but inhibited IR-induced expression of eNOS and intercellular adhesion molecule (ICAM)-1. At 10 weeks, while rats with IR alone had normal plasma Cr, kidneys displayed decreased peritubular capillary density with increased interstitial collagen, α-smooth muscle actin+ myofibroblasts, and F4/80+ macrophages. These changes were inhibited by miR-486-5p (CD31, collagen p<0.0001, n=6-8). Although blood pressure was similar across rat groups, IR inhibited endothelium-dependent vasorelaxation in mesenteric arteries at 10 weeks, which was prevented by miR-486-5p. Delayed administration of 2 doses of miR-486-5p (96hr, 3 weeks after IR) had no effect on capillary density, kidney fibrosis, blood pressure, or endothelial function. Conclusions: In rats, early administration of miR-486-5p prevents kidney IR injury and preserves regional blood flow despite reduction in eNOS expression. miR-486-5p also protects against CKD development and associated endothelial dysfunction. The results suggest that miR-486-5p is a promising therapy for the prevention of ischemic AKI and its complications. Funding: Private Foundation Support, 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) | 0.000 | 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 | 0.000 |
| 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".