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A role of Wnt/beta‐catenin signaling in the pathogenesis of renal interstitial fibrosis

Wnt proteins are a family of signaling regulators that play an essential role in embryonic kidney development; however, their expression in adult kidney is thought to be silenced. In this study, we report a comprehensive analysis of the expression and regulation of Wnts, their frizzled (Fzd) receptors and antagonists in normal and fibrotic kidneys after obstructive injury. The vast majority of 19 different Wnts and 10 Fzd receptor genes were expressed at various levels in mouse adult kidney. Except Wnt5b, Wnt8b and Wnt9b, all members of the Wnt family were up‐regulated with distinct dynamics in fibrotic kidney after unilateral ureteral obstruction. The expression of most Fzd receptors and Wnt antagonists was induced as well. A dramatic accumulation of beta‐catenin in renal tubular epithelial cell cytoplasm and nuclei was observed after obstructive injury, indicating the activation of the canonical pathway of Wnt signaling. Numerous Wnt/beta‐catenin target genes, such as c‐Myc, Twist, LEF1 and fibronectin, were induced, and their expression was closely correlated with renal beta‐catenin abundance. Delivery of Wnt antagonist Dickkopf‐1 gene significantly reduced renal beta‐catenin accumulation and inhibited the expression of Wnt/beta‐catenin target genes. Furthermore, gene therapy with Dickkopf‐1 inhibited myofibroblast activation, suppressed type I collagen and fibronectin expression, and reduced total collagen content in mouse model of obstructive nephropathy. These results suggest a pivotal role of Wnt/beta‐catenin signaling in the pathogenesis of renal fibrosis; therefore, targeting this signal pathway may be a novel strategy for therapeutic intervention of fibrotic kidney disorders.