Activins Facilitate TGF-β1 Profibrotic Signaling in Kidneys
Bibliographic record
Abstract
Background: Chronic kidney disease (CKD) is a rising health issue in North America. It is characterized by progressive renal fibrosis leading to end-stage kidney disease requiring dialysis or transplantation. TGFβ1 is a central mediator of kidney fibrosis in CKD of diverse etiology. Directly blocking it is unfeasible due to adverse effects. Alternate approaches to inhibit TGFβ1 signaling are needed to develop tolerable antifibrotic therapies. Recent studies suggest that TGFβ1 requires activins for its profibrotic effects. Interesingly, both signal through the same canonical Smad pathway. Here we study the mechanisms by which activins enable TGFβ1-induced fibrosis and assess efficacy of specific activin inhibition in vivo. Methods: Primary mouse kidney mesangial cells (MC) were used. Activin A and B (AA, AB), the predominant activins, were inhibited with a neutralizing antibody or follistatin. ELISA, IF and IB were used to assess cytokine levels, signaling pathways and profibrotic responses. Smad3 transcriptional activity was assessed by CAGA12 luciferase reporter and the alpha smooth muscle actin (αSMA) promoter luciferase. Unilateral ureteral obstruction (UUO) was created in mice overexpressing (OE) TGFβ1 or wild-type controls, and effects of neutralizing anti-AA antibody on kidney fibrosis was assessed. Results: TGFβ1 stimulated the production of AA more than AB, and AA neutralization inhibited the profibrotic effects of TGFβ1. TGFβ1 provoked strong early Smad3 activation (30-60min), while AA did so later (24-48h). Inhibition of AA decreased TGFβ1 (24h)-induced Smad3 activation, assessed by its phosphorylation, nuclear accumulation, and transcriptional activity. Cells retained responsiveness to AA signaling even after becoming refractory to TGFβ1 restimulation, enabling ongoing Smad3 activation. AA additionally regulated noncanonical TGFβ1 signaling. Its inhibition reduced nuclear accumulation of MRTFA, a Smad3 co-mediator of αSMA induction by TGFβ1. Fibrosis was augmented in TGFβ1 OE mice. Neutralizing AA attenuated Smad3 activation and fibrosis in both wild-type and TGFβ1 OE mice. Conclusions: AA facilitates TGFβ1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTFA) signaling. Importantly, AA inhibition reduced fibrosis in vivo, suggesting a novel potential therapeutic for fibrosis in CKD.
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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) | 0.003 | 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".