FP087DISTINCT GENE EXPRESSION PATTERNS IN EXPERIMENTAL RENAL ARTERY STENOSIS AND ISCHEMIA-REPERFUSION INJURY
Bibliographic record
Abstract
INTRODUCTION: Atherosclerotic renal artery stenosis is a common vascular disease affecting the elderly and is associated with increased morbidity and mortality due to cardiovascular and renal complications. Although the 2-kidney-1-clip murine model have been used to study renovascular hypertension, acute establishment of vascular obstruction raises a concern that the pattern of injury may not resemble that of human atherosclerotic renal artery stenosis. The objective of the study is to compare and contrast patterns of renal injury established by cuff placement, to induce renal artery stenosis (RAS), with acute vascular occlusion by clamping the renal artery in ischemia reperfusion (IR) injury. METHODS: RAS surgery was performed by placement of a polytetrafluoroethylene cuff on the right renal artery for 3 days (RAS, n= 5) and 7 days (7D RAS, n= 5). Renal ischemia was induced with non-traumatic clamps for 25 minutes through a midline abdominal incision (IR, n= 5). Sham surgery was performed without clamping or cuff placement (SH, n= 5). Kidneys were harvested at 3 days (IR, 3D RAS and SH) and 7 days (7D RAS) for assessment of histology. Global gene expression analysis was performed by RNA sequencing (RNA-Seq). Confirmation of gene expression was performed by Real-Time PCR. RESULTS: In the IR group, there was acute tubular necrosis with cellular sloughing and tubular cast formation. In contrast, renal cortex in 3D RAS showed minimal histopathologic change despite stable 70 % reduction in blood flow. At later time points (7D RAS), the cuffed kidneys showed interstitial fibrosis and tubular atrophy without tubular necrosis. The RNA-Seq analysis showed marked upregulation of pro-inflammatory and pro-oxidant genes in the IR group compared to 3D RAS, 7D RAS and SH groups. In the IR mice, real time PCR showed statistically significant induction of TNF (p< 0.0001 vs 3D RAS, 7D RAS, SH), TGFB1 (p< 0.0001 vs 3D RAS, 7D RAS, SH), IL6 (p=0.0006 vs 3D RAS, p=0.0004 vs 7D RAS, p=0.0003 SH), PLAUR (p< 0.0001 vs 3D RAS, 7D RAS, SH), and ANKRD1 (p< 0.0001 vs 3D RAS, 7D RAS, SH). CONCLUSIONS: We conclude that ischemia reperfusion injury and renal artery stenosis show strikingly different morphologic patterns of injury and gene expressions, particularly at early time points. There was no evidence of kidney injury and interstitial inflammation 3 days after cuff placement indicating that the kidney is capable of adapting to reduction in blood flow for a period of time—similar to human atherosclerotic renovascular disease. The lack of acute injury in the RAS model supports our hypothesis that this is a suitable model to study potential therapeutic interventions to prevent progressive renal and cardiac disease in patients with atherosclerotic renal artery stenosis.
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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".