Quercetin treatment reduces the severity of renal dysplasia in a beta-catenin dependent manner

• Published in: PloS one Vol. 15; no. 6; p. e0234375
• Main Authors: Cunanan, Joanna, Deacon, Erin, Cunanan, Kristina, Yang, Zifan, Ask, Antje, Morikawa, Lily, Todorova, Ekaterina, Bridgewater, Darren, Zegers, Mirjam M
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 17.06.2020; Public Library of Science (PLoS)
• Subjects: Biology and Life Sciences; Breast cancer; Care and treatment; Cell adhesion; Cell adhesion molecules; Children; Cytoplasm; Cytoskeletal proteins; Development and progression; Disease; Dysplasia; E-cadherin; Embryos; Explants; Flavonoids; Gene expression; Genes; Genetic aspects; Glial cell line-derived neurotrophic factor; Health aspects; Histopathology; Kidney diseases; Kidneys; Laboratories; Medicine; Medicine and Health Sciences; Morphogenesis; Nephrons; Neural cell adhesion molecule; Nuclei (cytology); Pathogenesis; Pathology; Pax2 protein; Quercetin; Renal failure; Research and Analysis Methods; SIX gene family; Ureter; Vimentin; β-Catenin; Canada; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0234375

Renal dysplasia, the major cause of childhood renal failure, is characterized by defective branching morphogenesis and nephrogenesis. Beta-catenin, a transcription factor and cell adhesion molecule, is markedly increased in the nucleus of kidney cells in human renal dysplasia and contributes to its pathogenesis by altering target genes that are essential for kidney development. Quercetin, a naturally occurring flavonoid, reduces nuclear beta-catenin levels and reduces beta-catenin transcriptional activity. In this study, we utilized wild type and dysplastic mouse kidney organ explants to determine if quercetin reduces beta-catenin activity during kidney development and whether it improves the severity of renal dysplasia. In wild type kidney explants, quercetin treatment resulted in abnormal branching morphogenesis and nephrogenesis in a dose dependent manner. In wild type embryonic kidneys, quercetin reduced nuclear beta-catenin expression and decreased expression of beta-catenin target genes Pax2, Six2, and Gdnf, which are essential for kidney development. Our RD.sup.B mouse model of renal dysplasia recapitulates the overexpression of beta-catenin and histopathological changes observed in human renal dysplasia. RD.sup.B kidneys treated with quercetin resulted in improvements in the overall histopathology, tissue organization, ureteric branching morphogenesis, and nephrogenesis. Quercetin treatment also resulted in reduced nuclear beta-catenin and reduced Pax2 expression. These improvements were associated with the proper organization of vimentin, NCAM, and E-cadherin, and a 45% increase in the number of developing and maturing nephrons. Further, our results show that in human renal dysplasia, beta-catenin, vimentin, and e-cadherin also have abnormal expression patterns. Taken together, these data demonstrate that quercetin treatment reduces nuclear beta-catenin and this is associated with improved epithelial organization of developing nephrons, resulting in increased developing nephrons and a partial rescue of renal dysplasia.