Targeting Angiopoietin-Tie2 Signaling in Kidney Ischemia-Reperfusion Injury
Bibliographic record
Abstract
Background: The endothelial angiopoietin (ANG)-Tie2 signaling pathway is required for vascular development and homeostasis. Dysregulation of ang-Tie2 pathway has been implicated in diseases including venous malformation, glaucoma, diabetic nephropathy, and septic acute kidney injury (AKI). The endothelial-specific phosphatase VE-PTP/PTPRB is a negative regulator of Tie2 phosphorylation. Here we investigate the therapeutic roles of Angiopoietin/Tie2 signaling in kidney ischemia-reperfusion injury (IRI). Methods: A bitransgenic doxycycline-inducible system (Veptpflox/flox, Rosa26-rtTA+/+, tetO-CreTg/+) was used to knockout VE-PTP at postnatal day 0 (VE-PTPiKO). Adult male VE-PTPiKO and littermate control mice underwent bilateral IRI or sham surgery. Serum creatinine was measured on day1, day3 and day7 after surgery by HPLC method. Data were analyzed using two-way ANOVA. Tissues were harvested on day 7 for histology, immunohistochemistry and RNA/protein analysis. Bulk RNAseq was performed with RNA extracted from whole kidney 5 hours after IRI. Normalization and differential expression were determined using DESeq2. For pharmacological studies, adult male C57BL/6J mice were used. A new soluble ANGPT1 mimetic (C4BP-ANG1) or vehicle were administered by intraperitoneal injection. Results: Western blot analysis showed VE-PTP protein levels were increased in kidneys post-IRI and following hypoxia-inducible factor stabilization. Genetic deletion of VE-PTP rescued declined Tie2 phosphorylation in kidney after IRI. While serum Creatinine was elevated 1day post-IRI in control mice, this increase was minimal in VE-PTP iKO mice (p=0.0055). Global gene expression analysis indicated minimal kidney transcriptome change at base line whereas in the setting of IRI, VEPTPiKO mice showed a less activated renal endothelium and downregulation of acute stress response gene signature. A corresponding decrease in pro-fibrotic genes was observed in VE-PTPiKO mice on day7. In the pharmacological study, systemic administration of C4BP-ANG1 activated Tie2 and its downstream AKT/eNOS/NO pathways in mouse kidney in physiological condition. Ongoing studies are analyzing its protective effect in ischemic AKI. Conclusions: Our data provide evidence for augmenting Tie2 activation-induced vascular protection as a promising therapeutic strategy for renal protection following IR-AKI. Funding: NIDDK Support
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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) | 0.000 | 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 | 0.001 |
| 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".