TDAG51 is a key modulator of vascular calcification and osteogenic transdifferentiation of arterial smooth muscle cells
Bibliographic record
Abstract
Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in patients with chronic kidney disease (CKD). More than half of all deaths from patients with end-stage renal disease (ESRD) requiring dialysis can be attributed to CVD. Although traditional risk factors for CVD are prevalent in ESRD, they cannot fully explain the high mortality rates. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced CKD and is now recognized as an important predictor and an independent risk factor for cardiovascular and all-cause and mortality in these patients. VC in CKD is triggered by vascular smooth muscle cells (VSMCs) transforming into osteoblasts, a consequence of elevated circulating phosphate levels due to poor kidney function. Understanding and targeting this SMC trans-differentiation and subsequent VC represents a viable therapeutic avenue for managing CKD complications. Similar to bone formation, VC is a highly regulated process that draws many parallels with osteogenic differentiation. We have recently observed that T-cell Death Associated Gene 51 (TDAG51), a protein upregulated by oxidative and endoplasmic reticulum stress, is induced in SMCs under conditions of hyperphosphatemia and is expressed in the medial layer of calcified human vessels. We have found that ablation of TDAG51 reduces SMC trans-differentiation and VC, both in human SMCs treated with TDAG51 siRNA and in mouse VSMCs isolated from TDAG51−/− aortas. To explain these findings, we observed that TDAG−/− VSMCs express reduced levels of the of the Pit-1, a solute transporter responsible for cellular phosphate uptake. Consistent with this observation, reduced Pit-1 expression was associated with reduced intracellular phosphate levels and reduced phosphate-induced apoptosis. Further, TDAG−/− VSMCs exhibit significantly reduced transcriptional activity of a phosphate-inducible transcription factor, and well-established driver of VC, known as Runx2. Support or Funding Information This work was supported in part by research grants to Richard C. Austin from the Heart and Stroke Foundation of Ontario (T-6146), the Heart and Stroke Foundation of Canada (G-13-0003064 and G-15-0009389) and the Canadian Institutes of Health Research (74477). TDAG51 is involved in the development and progression of VC through the regulation of intracellular phosphate content and Runx2 transcriptional activity. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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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".