Quercetin as a Novel Treatment for Developmental Abnormalities of the Kidney
Bibliographic record
Abstract
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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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) | 0.002 | 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".