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

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 RD B mouse model of renal dysplasia recapitulates the overexpression of beta-catenin and histopathological changes observed in human renal dysplasia. RD 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.

Shroom3, a Gene Associated with CKD, Modulates Epithelial Recovery after AKI

“…These data suggest a large number of damaged cells are being removed during the initial stages of re-establishing the functional epithelium (38,39). As the damaged cells are removed, there is an onset of mesenchymal cell marker expression such as vimentin and NCAM, which indicates epithelial-to-mesenchymal transition (40,41,42). At 48 hours after IRI, vimentin and NCAM expression are observed in the tubular epithelium in both WT and Shroom3 Gt/+ kidneys (Figure 3, E, G, I, and K).…”

“…Kidneys were resected 48 hours and 10 days after ischemia/reperfusion, and fixed in 4% paraformaldehyde for 24 hours, processed for histology, and stained with H&E, PAS, and PSR (Sigma Aldrich, Oakville, ON, Canada). Immunohistochemistry (IHC) and immunofluorescence was performed as described (41). For mouse monoclonal primary antibodies, mouse-on-mouse blocking reagents (Vector Laboratories, Burlingame, CA, USA) were used, per manufacturer protocols.…”

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“…The study also reported that quercetin treated rats showed reduced inflammation by preventing phosphoinositide 3-kinase (PI3 k)/Akt (protein kinase B) signaling pathway by targeting phosphoinositide 3-kinase regulatory subunit 1 (PIK3 R1) and reduced expression NLRP3, p-PI3 k, Phospho-Akt (p-Akt), and caspase1 in kidney tissues [57]. Another study reported that in a mouse model of renal dysplasia, quercetin treatment increased the epithelial organization of developing nephrons, inhibited nuclear beta-catenin, and thus improved renal dysplasia [58]. A report showed that combined pretreatment of 30 mg/kg resveratrol and 50 mg/kg quercetin over a period of seven days prevented paracetamol-induced (2 g/kg body weight) acute renal failure via reducing plasma creatinine, urea, and inflammatory markers (e.g., MDA, IL-6, and TNF-α) [59].…”