UNDERSTANDING HOW ACTIVINS CONTRIBUTE TO TGFß1 PROFIBROTIC SIGNALIING IN CHRONIC KIDNEY DISEASE
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Bibliographic record
Abstract
Chronic kidney disease (CKD) affects around 11% of people in North America and is expected to rise. CKD is characterized by the development of fibrosis requiring kidney transplant or dialysis to survive as a direct result of impaired kidney function. TGFβ1 is a prominent profibrotic mediator in this context and is secreted by mesangial cells, tubular cells and fibroblasts. These cells once activated contribute to excessive production of extracellular matrix (ECM) proteins deteriorating functional renal tissue. The direct inhibition of TGFβ1 has limitations due to adverse effects in humans that alternative methods have gain popularity. Here, we discover activin A (actA), a member of TGFβ1 superfamily, playing a crucial role in sustaining the chronic effects of TGFβ1. Activins are multifunctional secreted cytokines synthesized as homo- or hetero-dimers of inhibin β subunits A, B, C or E. Previously, there have been attempts at blocking actA using various inhibitors such as a naturally occurring antagonist called follistatin (FST), ActRIIA/B trap and antibody. However, there is the risk of uncertain side effects due to their non specificity in blocking other ligands important to various cellular processes. Similarly, other variants of activins such as actAC has been shown to abrogate actA-induced pSmad2/3 signaling however little is known about their long-term effects. It is important to note that actA has been found highly elevated in serum and kidneys from human and mice with CKD. We hypothesize that actA regulates both canonical and noncanonical pathways to control TGFβ1-induced profibrotic responses. In the first study, within mesangial cells (MCs), the profibrotic effects of TGFβ1 are sustained primarily through the secretion of actA as it promotes Smad3 phosphorylation and transcriptional activity when MCs exhibit reduced sensitivity to TGFβ1 but not actA. This in part is facilitated by actA upregulating TGFβ1 receptor type II helping continue downstream signaling. Furthermore, actA enhances transcription through activation of MRTF-A, Smad3 co-activator fibrotic genes. Notably, actA neutralization effectively inhibits fibrosis induced by unilateral ureteral obstruction (UUO) in wildtype mice. Interestingly, TGFβ1-overexpressing mice with CKD (UUO) exhibit worsened fibrosis, accompanied by increased renal expression of actA and that its neutralization mitigated these outcomes. In the second study, we established a novel 5/6 nephrectomy animal model overexpressing TGFβ1 in C57BL/6 background mice resistant to hypertension and fibrosis to directly assess for actA faciliatory role in the maladaptive epithelial-mesenchymal crosstalk from long-term tubulointerstitial fibrosis caused by TGFβ1. TGFβ1 induces secretion of actA from tubular cells and actA neutralization prevents TGFβ1 profibrotic response in renal fibroblasts, interestingly, through Smad3 and YAP. This led us to our third study, which was to investigate TGFβ1’s regulation of the actA gene (INHBA). Results reveal critical transcription factors (Stat5, Foxp1 and Smad3) controlling actA promoter activity within 350 bp region of actA promoter. Targeting actA inhibition shows promise as an antifibrotic approach with potentially better clinical tolerability than direct TGFβ1 inhibition.
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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 | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 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 it