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

Joanna Cunanan,Lily Morikawa,Erin Deacon,Darren Bridgewater,Kristina Cunanan,Antje Ask,Zifan Yang,Ekaterina Todorova,Mirjam M. Zegers

doi:10.1371/journal.pone.0234375

Abstract

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.

Highlights

Renal dysplasia is a developmental disorder of the kidney and affects approximately 0.1% of live births and 2% at paediatric autopsy [1,2,3,4,5]
Our previous studies have demonstrated that beta-catenin overexpression contributes to severe renal dysplasia in both the human condition and mouse model [14,15,16] identifying factors that can reduce beta-catenin can contribute to improvements in the severity of renal dysplasia
Our work demonstrated that transgenic mouse models that overexpress beta-catenin result in the dysregulation of the normal genetic programs required for kidney development and as a result contributes to the genesis of renal dysplasia [14,15,16]

Summary

Introduction

Renal dysplasia is a developmental disorder of the kidney and affects approximately 0.1% of live births and 2% at paediatric autopsy [1,2,3,4,5]. Dysplastic kidneys can exhibit disorganized and incomplete collecting duct and nephron formation, poorly differentiated epithelial tubules surrounded by a fibromuscular collar, metaplastic cartilage transformation, cystic glomeruli, and expanded loosely packed renal stroma. These abnormalities can be unilateral or bilateral (affecting one or both kidneys) and can be diffuse (involving the entire kidney), segmental (involving segments of the kidney) or focal (affected regions are surrounded by normal tissue) [1,2,3,4,5]

Methods

Results

Conclusion