Quercetin as a Novel Treatment for Developmental Abnormalities of the Kidney
Notice bibliographique
Résumé
Renal dysplasia is the abnormal development of the kidney and is the leading cause of chronic kidney disease and kidney failure in children. Despite this, there is no cure. Invasive symptom management such as dialysis and kidney transplants have significant adverse effects. Normal kidney development involves the interaction between three cell types: ureteric epithelium, metanephric mesenchyme, and renal stroma. The ureteric epithelium undergoes branching morphogenesis to form the collecting system, and the metanephric mesenchyme undergoes nephrogenesis to form the nephrons. The renal stroma provides structural support to the developing kidney and regulates proper branching morphogenesis and nephrogenesis. Beta‐catenin is a transcription factor essential for normal branching morphogenesis and nephrogenesis. In human renal dysplasia, beta‐catenin levels are markedly increased in the nucleus of the stroma, mesenchyme and epithelium. Our findings from transgenic mouse models show that elevated levels of beta‐catenin in the nucleus cause dysregulation of genes leading to abnormal branching morphogenesis and nephrogenesis, resulting in renal dysplasia. Our objective is to inhibit beta‐catenin transcriptional activity in the kidney and determine its effects on normal and dysplastic kidney development. Quercetin is a flavonoid that inhibits beta‐catenin activity and was effective in reducing beta‐catenin levels that resulted to improved outcomes in different cancer types and in kidney fibrosis. We tested if Quercetin alters beta‐catenin activity during normal kidney development. Wild‐type embryonic day 13.5 mouse kidneys were cultured in growth medium supplemented with 0uM (control), 40uM, 80uM, and 160uM Quercetin for 48 hours. A dose‐dependent disruption in branching morphogenesis and nephrogenesis was observed by performing immunofluorescence for cytokeratin, Pax2, and Six2. In addition, quantitative reverse‐transcriptase PCR (qRT‐PCR) showed a disrupted expression of beta‐catenin target genes essential for kidney development (Pax2, Wnt4, and GDNF). Consistent with these findings, immunohistochemistry for beta‐catenin demonstrated that Quercetin reduced nuclear beta‐catenin expression and increased cytoplasmic expression in a dose‐dependent manner. Next, to determine if Quercetin rescues renal dysplasia, we utilized transgenic mice models that over‐express beta‐catenin specifically in the kidney stroma ( Foxd1;B‐cat GOFs ), or in the mesenchyme, stroma, and ureteric epithelium ( Rarb2;B‐cat GOFsmu ). Both of these animal models have severe renal dysplasia characterized by disorganized branching morphogenesis and disrupted nephrogenesis. Immunofluorescence for cytokeratin and Pax2 showed that in‐vitro treatment of embryonic day 13.5 dysplastic kidneys with 40uM Quercetin resulted in a markedly improved kidney with improved branching morphogenesis and nephrogenesis, and closely resembles wild‐type kidney development. Our findings demonstrate that Quercetin reduces beta‐catenin activity in normal and dysplastic kidneys, reduces the transcription of genes that play central roles in kidney development, and resulted to a reduced severity of renal dysplasia. Support or Funding Information NSERC, CIHR and KFOC This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
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 ».