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β-catenin causes renal dysplasia via upregulation of Tgfβ2 and Dkk1.

ABSTRACT: Renal dysplasia, defined by defective ureteric branching morphogenesis and nephrogenesis, is the major cause of renal failure in infants and children. Here, we define a pathogenic role for a β-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of β-catenin in the ureteric cell lineage before the onset of kidney development increased β-catenin levels and caused renal aplasia or severe hypodysplasia. Analysis of gene expression in the dysplastic tissue identified downregulation of genes required for ureteric branching and upregulation of Tgfβ2 and Dkk1. Treatment of wild-type kidney explants with TGFβ2 or DKK1 generated morphogenetic phenotypes strikingly similar to those observed in mutant kidney tissue. Stabilization of β-catenin after the onset of kidney development also caused dysplasia and upregulation of Tgfβ2 and Dkk1 in the epithelium. Together, these results demonstrate that elevation of β-catenin levels during kidney development causes dysplasia.

SUBMITTER: Bridgewater D

PROVIDER: S-EPMC3065227 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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β-catenin causes renal dysplasia via upregulation of Tgfβ2 and Dkk1.

Bridgewater Darren D Di Giovanni Valeria V Cain Jason E JE Cox Brian B Jakobson Madis M Sainio Kirsi K Rosenblum Norman D ND

Journal of the American Society of Nephrology : JASN 20110324 4

Renal dysplasia, defined by defective ureteric branching morphogenesis and nephrogenesis, is the major cause of renal failure in infants and children. Here, we define a pathogenic role for a β-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of β-catenin in the ureteric cell lineage before the onset of kidney development increased β-catenin levels and caused renal aplasia or severe hypodysplasia. Analysis of gene expression in the dysplastic tissue identified downregula ...[more]

PMID: 21436291

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Project description: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.

Project description:BackgroundMesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.MethodsThe effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.ResultsOur results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.ConclusionsThe eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.

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β-catenin causes renal dysplasia via upregulation of Tgfβ2 and Dkk1.

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β-catenin causes renal dysplasia via upregulation of Tgfβ2 and Dkk1.

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