B-007 Activin A is a potential mediator of TGFß1-induced tubulointerstitial fibrosis
Bibliographic record
Abstract
Abstract Background Chronic kidney disease (CKD) is a rising health issue in North America, characterized by progressive renal fibrosis often leading to organ failure. TGFß1 is a central mediator of fibrosis in CKD of diverse etiology, but its direct inhibition is limited by adverse effects. We recently showed in glomerular mesangial cells (MC) that activin A (ActA) mediates TGFß1 profibrotic effects through regulation of both canonical Smad3 and noncanonical MRTF-A signaling. Here we study the potential role of ActA in the development of tubulointerstitial fibrosis (TIF), a major determinant of kidney function decline in CKD. We further assess the promoter regulation of ActA by TGFß1. Methods Renal fibrosis was induced in mice overexpressing (OE) TGFß1 using 2 models: 5/6 nephrectomy (Nx) and unilateral ureteral obstruction (UUO). UUO mice were treated with a neutralizing ActA antibody to assess effects on fibrosis. Primary mouse MC, human renal proximal tubular epithelial cells (PTEC, HK2) and rat renal fibroblasts (RF) were used. ActA and Activin B (ActB) were inhibited with a neutralizing antibody or follistatin. Transcriptional activity of the ActA promoter was studied using a luciferase reporter plasmid and a series of deletion constructs. Results TGFß1 OE augmented fibrosis and activin levels in Nx and UUO. ActA neutralization inhibited Smad3 activation and fibrosis after UUO in wild-type and TGFß1 OE mice. In both models, ActA and B were significantly increased in tubular cells, which largely colocalized to PTEC identified by megalin. We thus studied the potential role of activins in tubular-fibroblast crosstalk. TGFß1 increased secretion of ActA and B from HK2 cells, with a greater ActA effect. Media from HK2 treated with TGFß1 induced RF Smad3 activation and fibrotic responses (matrix synthesis, aSMA induction). These were blocked by follistatin or ActA, but not ActB, neutralization. In MC, we found the -350bp region of the ActA promoter is required for TGFß1 regulation. Interestingly, a novel CT microsatellite site upstream of this which suppressed promoter activity was also identified. Conclusion ActA is induced by TGFß1 and mediates its profibrotic effects, with relevance to both glomerular and TIF. Its inhibition is being evaluated as a novel treatment for fibrosis in CKD.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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) | 0.001 | 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 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".