DNase-1 Exerts Protective Effects after Severe Kidney Ischemia-Reperfusion Injury
Bibliographic record
Abstract
Background: Kidney Injury Molecule-1 (KIM-1) is a transmembrane receptor expressed by proximal tubular epithelial cells during injury. KIM-1 recognizes phosphatidylserine, an “eat me” signal that marks apoptotic cells for phagocytic clearance. Notwithstanding that, severe acute injury (AKI) leads to persistent KIM-1 expression and drives fibrosis. Herein, we design a study to evaluate whether DNase1 contribute to the pathogenesis of KIM-1- mediated renal fibrosis. Methods: To assess the functional role of KIM-1 expression, KIM-1+/+, KIM-1-/-, and Tim1fl/fl SLC34a1 C57BL/6 mice were subjected to both moderate (25 minutes) and severe (45 minutes) unilateral ischemia reperfusion injury (UIRI). Kidneys were isolated after 3, 7, 28, and 42 days of reperfusion to assess histology and markers of injury and fibrosis. To examine gene expression profile, RNA sequencing of kidneys from KIM-1+/+ and KIM-1-/- mice after 45 min UIRI was performed. DNase1 expression and activity was assessed by using in situ and in vitro analyses of kidneys and sera. To test the therapeutic potential of DNase1 after severe UIRI, mice received repeated doses of DNase1 (2 mg/kg) or vehicle-solution (NaCl 0.9%). Results: Our data indicate that by clamping the renal pedicle for 45 min and following the mice for 42 days, the injured KIM-1+/+ kidneys were markedly reduced in size and fibrotic compared with control kidneys. By contrast, the injured KIM-1-/- kidney recovered completely. The fibrotic phenotype was not observed with the moderate injury model. Also, a strong upregulation of mRNA encoding a panel of cytokines and growth factors was observed at both 7 and 42 days after injury in KIM-1+/+ kidney compared with KIM-1-/-. This highlights the possibility that KIM-1 might directly regulate epithelial cytokine and fibrotic marker expression. In addition, DNase1 was among the top downregulated genes in the KIM-1+/+ kidney exposed to severe injury. Renal DNase1 expression was completely abrogated in KIM-1+/+ kidney compared to KIM-1-/- kidney at all time points analysed. Early decline of DNase1 activity directly correlated with lower injury score and fibrosis. DNase-1 treatment significantly reduced the pro-inflammatory response and histopathological changes observed in KIM-1+/+ kidney after severe AKI. Conclusion: DNase1 therapy is protective following severe AKI and attenuates murine kidney fibrosis. 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 | 0.000 |
| 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) | 0.002 | 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".