miR-486-5p Protects Against Ischemic AKI in Rat but Inhibits eNOS and Angiogenesis
Bibliographic record
Abstract
Background: Acute kidney injury (AKI) is a common complication of hospitalization for which no effective treatments exist. Patients with recovered AKI are at increased risk of progressive chronic kidney disease (CKD). In ischemia-reperfusion (IR) AKI, endothelial injury contributes to capillary rarefaction and development of tubulointerstitial fibrosis. We previously showed that microRNA (miR)-486-5p protects against IR AKI in mice associated with targeting of phosphatase and tensin homolog (PTEN), activation of Akt, and downregulation of genes involved in apoptosis and tumor necrosis factor signaling in proximal tubular cells. However, the effects of miR-486-5p in rat IR AKI and on endothelial cell injury are unknown. Methods: Kidney ischemic injury was induced in male rats by 45-min bilateral renal artery clamping followed by reperfusion, with outcomes after 24hr, 48hr, and 4 weeks. Lipid-encapsulated miR-486-5p (0.5mg/kg) was administered via tail vein injection at the start of reperfusion. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-486-5p (1nM), and angiogenesis was evaluated with matrigel-based tube formation assay. Results: Administration of miR-486-5p to rats with IR injury significantly protected against AKI with normalization of plasma Cr and BUN (p<0.05, n=3), and reduced KIM-1 levels (p<0.01, n=3) at 24 and 48hr. In rats with AKI, miR-486-5p did not affect plasma Cr after 4 weeks, compared to sham rats or rats with AKI alone. However, in rats with AKI, miR-486-5p protected against the development of interstitial fibrosis and tubular atrophy at 4 weeks. In HUVECs, miR-486-5p decreased the expression of PTEN (p<0.05, N=4), and endothelial nitric oxide synthase (eNOS) (p<0.001, N=4). Matrigelbased network formation assay showed that miR-486-5p reduced the angiogenic activity of normoxic HUVECs compared to untreated cells or cells treated with scramble miRNA (p<0.05, N=4). Conclusions: These data suggest that miR-486-5p prevents ischemic AKI in rats, and protects against the development of CKD after AKI. However, miR-486-5p may affect endothelial function with reduced angiogenic activity, possibly related to decreased eNOS expression. Although miR-486-5p shows promise as a therapeutic tool in AKI, long-term effects on kidney microvascular structure and function in vivo require further study. Funding: 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| 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".