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Wnt/β-Catenin Signaling Promotes Renal Interstitial Fibrosis

Weichun He^*,, Chunsun Dai^*, Yingjian Li^*, Gang Zeng^*, Satdarshan P. Monga^* and Youhua Liu^*

^* Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Department of Medicine, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China

Correspondence: Dr. Youhua Liu, Department of Pathology, University of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: 412-648-8253; Fax: 412-648-1916; E-mail: liuy{at}upmc.edu

Received for publication June 4, 2008. Accepted for publication October 28, 2008.

Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of β-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/β-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal β-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal β-catenin accumulation and inhibited the expression of Wnt/β-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/β-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.

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