Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
PLoS One. 2020 Jun 17;15(6):e0234375. doi: 10.1371/journal.pone.0234375. eCollection 2020.
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 RDB mouse model of renal dysplasia recapitulates the overexpression of beta-catenin and histopathological changes observed in human renal dysplasia. RDB 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.
肾发育不良是儿童肾衰竭的主要原因，其特征是分支形态发生和肾发生缺陷。β-连环蛋白（β-catenin）是一种转录因子和细胞黏附分子，在人类肾发育不良的肾细胞核中显著增加，并通过改变对肾脏发育至关重要的靶基因来促进其发病机制。槲皮素是一种天然存在的类黄酮，可降低核β-连环蛋白水平并降低β-连环蛋白的转录活性。在这项研究中，我们利用野生型和发育不良的鼠肾器官外植体来确定槲皮素是否在肾脏发育过程中降低β-连环蛋白的活性，以及它是否改善肾发育不良的严重程度。在野生型肾脏外植体中，槲皮素处理以剂量依赖的方式导致异常的分支形态发生和肾发生。在野生型胚胎肾脏中，槲皮素降低核β-连环蛋白表达，并降低β-连环蛋白靶基因 Pax2、Six2 和 Gdnf 的表达，这些基因对肾脏发育至关重要。我们的 RDB 鼠肾发育不良模型再现了β-连环蛋白的过度表达和人类肾发育不良中观察到的组织病理学变化。用槲皮素处理 RDB 肾脏可改善整体组织病理学、组织组织、输尿管分支形态发生和肾发生。槲皮素处理还导致核β-连环蛋白和 Pax2 表达减少。这些改善与波形蛋白、NCAM 和 E-钙黏蛋白的适当组织有关，并使发育和成熟的肾单位数量增加了 45%。此外，我们的结果表明，在人类肾发育不良中，β-连环蛋白、波形蛋白和 E-钙黏蛋白也存在异常表达模式。总之，这些数据表明，槲皮素处理可降低核β-连环蛋白，这与发育中的肾单位上皮组织的改善有关，从而导致发育中的肾单位数量增加，并部分挽救肾发育不良。
