UNDERSTANDING HOW ACTIVINS CONTRIBUTE TO TGFß1 PROFIBROTIC SIGNALIING IN CHRONIC KIDNEY DISEASE
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».