Bibliographic record
Abstract
Introduction: Chronic kidney disease (CKD) affects 10-15% of the world population, and 30-40 million people in the U.S. alone, posing an enormous medical and financial burden. We recently published that Hippo pathway nuclear effector, TAZ, is highly upregulated in renal tubules of the injured kidneys and promotes fibrotic tubular dysfunction. Renal tubules primarily depend on fatty acid oxidation to maintain homeostasis under normal conditions; however, renal injury and hypoxia trigger metabolic alterations (e.g., glycolysis activation). Although upstream controls are not clear, induction of glycolysis contributes to CKD in kidney injury. We tested the hypothesis that TAZ is a novel inducer of pathogenic renal glycolysis. Methods: We created HK-2 human renal epithelial cells stably expressing either a TAZ expression construct or control vector (driven by a CMV promoter) to mimic persistent TAZ induction during renal injury. Western blot analysis was utilized to confirm TAZ upregulation and examine changes in glycolytic enzymes between the transgenic cell types. To determine the involvement of Rac-GTPase pathway in TAZ-induced metabolic alterations, CMV-TAZ cells were treated with a Rac-Inhibitor, EHT1684 or vehicle control (water) for 1-2 days prior to western blot assessments for metabolic and fibrotic markers. Results: Renal tubular TAZ overexpression leads to robust upregulation of enzymes involved in the non-reversible steps of glycolysis (e.g., hexokinase, phosphofructokinase, and pyruvate kinase) and fibrotic factors (e.g., fibronectin, collagen-1 and CTGF induction). Sustained TAZ expression also promotes constitutively active Rac-1 isoform, Rac-1b, compared to control (vector) cells. TAZ-mediated induction of glycolytic enzyme/s and fibrotic molecules can be dramatically attenuated by pharmacologic inhibition of Rac activation with EHT1684. Conclusions: We demonstrated that TAZ expression promotes fibrotic and glycolytic reprogramming, identifying TAZ as a novel regulator of renal glycolysis. Rac activation downstream of TAZ is critical for both fibrotic and glycolytic reprogramming. Thus, TAZ and Rac may be attractive targets to suppress metabolic shifts and the prevalence of CKD (for which there are limited therapies).
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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 | 0.032 | 0.035 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.004 | 0.000 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.003 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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; both teacher heads agree on what is shown here.
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".