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• W2894426551 abstract "Polycystic kidney disease (PKD) results from excessive renal epithelial cell proliferation, leading to the formation of large fluid filled cysts which impair renal function and frequently lead to renal failure. Hyperactivation of numerous signaling pathways is hypothesized to promote renal epithelial cell hyperproliferation including mTORC1, extracellular signal-regulated kinase (ERK) and WNT signaling. β-catenin and its target genes are overexpressed in some PKD models and expression of activated β-catenin induces cysts in mice; however, β-catenin murine knockout studies indicate it may also inhibit cystogenesis. Therefore, it remains unclear whether β-catenin is pro- or anti-cystogenic and whether its role is canonical WNT signaling-dependent. Here, we investigate whether β-catenin deletion in a PKD model with hyperactived β-catenin signaling affects disease progression to address whether increased β-catenin drives PKD. We used renal epithelial cell specific Inpp5e-null PKD mice which we report exhibit increased β-catenin and target gene expression in the cystic kidneys. Surprisingly, co-deletion of β-catenin with Inpp5e in renal epithelial cells exacerbated polycystic kidney disease and renal failure compared to Inpp5e deletion alone, but did not normalize β-catenin target gene expression. β-catenin/Inpp5e double-knockout kidneys exhibited increased cyst initiation, cell proliferation and MEK/ERK signaling compared to Inpp5e-null, associated with increased fibrosis, which may collectively contribute to accelerated disease. Therefore, increased β-catenin and WNT target gene expression are not necessarily cyst promoting. Rather β-catenin may play a dual and context-dependent role in PKD and in the presence of other cyst-inducing mutations (Inpp5e-deletion); β-catenin loss may exacerbate disease in a WNT target gene-independent manner." @default.
• W2894426551 created "2018-10-05" @default.
• W2894426551 creator A5001840176 @default.
• W2894426551 creator A5023565912 @default.
• W2894426551 creator A5041760575 @default.
• W2894426551 creator A5047531486 @default.
• W2894426551 creator A5048353848 @default.
• W2894426551 creator A5071786017 @default.
• W2894426551 creator A5074593098 @default.
• W2894426551 date "2018-09-28" @default.
• W2894426551 modified "2023-09-27" @default.
• W2894426551 title "β-catenin ablation exacerbates polycystic kidney disease progression" @default.
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