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Wnt/-Catenin Signaling Promotes Renal Interstitial Fibrosis

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Wnt/-Catenin Signaling Promotes Renal Interstitial Fibrosis BASIC RESEARCH www.jasn.org Wnt/␤-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; †Department of Medicine, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China ABSTRACT 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 ␤-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/␤-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal ␤-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal ␤-catenin accumu- lation and inhibited the expression of Wnt/␤-catenin target genes. Furthermore, gene therapy with Dick- kopf-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/␤-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target. J Am Soc Nephrol 20: 765–776, 2009. doi: 10.1681/ASN.2008060566 The Wnt family of secreted signaling proteins plays hancer-binding factor (LEF) to stimulate the tran- an essential role in organogenesis, tissue homeosta- scription of Wnt target genes.5–7 In addition to this sis, and tumor formation.1–4 Aberrant regulation of canonical pathway, Wnt proteins may exert their Wnt signaling has been implicated in the pathogen- activities through numerous ␤-catenin–indepen- esis of many human diseases in diverse types of tis- dent, noncanonical intracellular signaling routes.8 sues.3,4 Wnt proteins transmit their signal across the Both Wnts and Fzd receptors are encoded by plasma membrane through interacting with ser- multiple, distinct genes, creating a complex net- pentine receptors, the Frizzled (Fzd) family of pro- work of signaling system with enormous degree of teins, and co-receptors, members of the LDL recep- tor–related protein (LRP5/6). Upon binding to Received June 4, 2008. Accepted October 28, 2008. their receptors, Wnt proteins induce a series of downstream signaling events involving Disheveled Published online ahead of print. Publication date available at www.jasn.org. (Dvl), axin, adenomatosis polyposis coli, and glyco- ␤ Correspondence: Dr. Youhua Liu, Department of Pathology, Uni- gen synthase kinase 3 , resulting in dephosphory- versity of Pittsburgh, S-405 Biomedical Science Tower, 200 Lo- lation of ␤-catenin. This leads to the stabilization of throp Street, Pittsburgh, PA 15261. Phone: 412-648-8253; Fax: ␤-catenin, rendering it to translocate into the nu- 412-648-1916; E-mail: [email protected] clei, where it binds to T cell factor/lymphoid en- Copyright ᮊ 2009 by the American Society of Nephrology J Am Soc Nephrol 20: 765–776, 2009 ISSN : 1046-6673/2004-765 765 BASIC RESEARCH www.jasn.org diversity as well as redundancy. At least 19 distinct Wnt proteins and 10 different Fzd receptors have been identified in mouse9,10 (see The Wnt Homepage http://www. stanford.edu/ϳrnusse/wntwindow.html). Not surprising, Wnt signaling is tightly reg- ulated in a multitude of ways. There are several secreted antagonists of Wnt signal- ing, including soluble Frizzled-related pro- tein (sFRP), Wnt inhibitory factor, and a family of Dickkopf (DKK) proteins.1,5 Of them, DKK proteins are unique in that they specifically inhibit the canonical Wnt signal pathway by binding to the LRP5/6 compo- nent of the receptor complex.11,12 Wnt/␤-catenin signaling has been shown to play a role in kidney development and dis- eases. Wnt4 and Wnt9b are highly expressed in the early stage during kidney develop- ment and are functionally important for nephron formation.13,14 In adult kidney, however, Wnt signaling seems to be si- lenced.14–16 Dysregulation of Wnt/␤-cate- nin signaling occurs in certain types of kid- ney diseases, including obstructive neph- 17,18 ropathy. These observations clearly sug- Figure 1. Expression of Wnt genes in normal and fibrotic mouse kidneys. (A) Repre- gest a potential role of Wnt signaling in mam- sentative RT-PCR results show the expression of different Wnt genes in normal mouse malian nephrogenesis, tissue homeostasis, kidney. In the absence of RT, no PCR product was detected, suggesting the specificity. and pathogenesis of kidney diseases; how- (B) Representative RT-PCR results demonstrate the steady-state levels of renal Wnt ever, the expression of 19 Wnts and 10 Fzd mRNA at different time points after UUO as indicated. Numbers (1, 2, and 3) indicate receptors in adult kidney remains to be deter- each individual animal in a given group. (C) Graphic presentation shows the distinct, mined. Furthermore, their regulation and dynamic pattern of Wnt regulation in the fibrotic kidney. Different Wnts with similar function in the evolution of chronic kidney dynamic pattern after injury were grouped. The actual values of relative mRNA levels diseases are poorly understood. (fold induction over sham controls) are presented in Supplemental Table 1. In this study, we performed a compre- hensive analysis of the expression and regulation of Wnts and 1A, the vast majority of 19 Wnts, except Wnt3a, Wnt8a, and their receptors and antagonists in normal and fibrotic kidneys Wnt10b, were expressed at different levels in mouse adult kid- after obstructive injury. Our data indicate that the majority of ney. In the absence of RT, no PCR product was detected, sug- Wnts and Fzd receptors are upregulated in diseased kidney, gesting the specificity of Wnt expression. We next investigated which leads to a dramatic accumulation of ␤-catenin, resulting the regulation of Wnt expression during the course of renal in induction of the Wnt/␤-catenin target genes. Furthermore, interstitial fibrosis induced by unilateral ureteral obstruction we show that delivery of Wnt antagonist DKK1 gene reduces (UUO). As shown in Figure 1B, the steady-state mRNA levels ␤-catenin accumulation and attenuates renal interstitial fibro- of most Wnt genes were increased at different time points after sis in a mouse model of obstructive nephropathy. These studies UUO. The actual values of renal mRNA levels of various Wnts establish a critical role of hyperactive Wnt/␤-catenin signaling are presented in the Supplemental Table 1. On the basis of the in the pathogenesis of renal fibrosis and present a novel target characteristic features of Wnt regulation, four dynamic pat- for therapeutic intervention of fibrotic kidney diseases. terns of Wnt expression during the process of renal fibrosis could be classified. As presented in Figure 1C, there were only three Wnts, including Wnt5b, Wnt8b, and Wnt9b, whose ex- RESULTS pression was unaltered throughout the course of renal fibro- genesis after UUO. Wnt1, Wnt7a, and Wnt7b displayed a sim- Expression of Wnt Genes in Normal and Fibrotic Kidneys ilar expression pattern, with a peak induction at 7 d after We first performed a systematic analysis of the mRNA expres- obstructive injury, followed by declining in mRNA levels. The sion of all Wnt genes in normal mouse kidney by the reverse expression of five other Wnts, including Wnt2b, Wnt3, Wnt5a, transcriptase–PCR (RT-PCR) approach. As shown in Figure Wnt9a, and Wnt16, was initially increased up to 7 d and sus- 766 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 765–776, 2009 www.jasn.org BASIC RESEARCH tained thereafter. The remaining eight members of Wnt family shared a comparable induction dynamic, with a continuous increase in mRNA expression during the entire experimental period. Of interest, there was no single Wnt whose expression was suppressed in the fibrotic kidney after UUO. Wnt protein was also upregulated in the fibrotic kidney. Figure 2 shows the protein levels of Wnt4 and Wnt7a at differ- ent time points after UUO. Similar to their mRNA, substantial increase in renal Wnt4 and Wnt7a protein abundance was ev- ident in a time-dependent manner. Of note, Wnt4 and Wnt7a protein also exhibited distinct patterns of induction dynamics (Figure 2). To address whether Wnt induction is a general phe- nomenon in renal fibrogenesis, we also examined Wnt expres- sion in a mouse model of adriamycin nephropathy. As pre- Figure 2. Induction of renal Wnt4 and Wnt7a protein expres- sented in Supplemental Figure 1, the expression of many Wnts sion after obstructive injury. Whole-kidney homogenates were was also upregulated in diseased kidney at 5 wk after injection prepared at different time points after UUO as indicated and of adriamycin, a time point when significant glomerular and immunoblotted with antibodies against Wnt4, Wnt7a, and interstitial fibrosis is evident.19 glyceraldehyde-3-phosphate dehydrogenase (GAPDH), re- spectively. Numbers (1 and 2) indicate each individual animal Regulation of Wnt Receptors and Antagonists in a given group. We next examined the expression of the Fzd receptor genes in mouse kidney. As shown in Figure 3A, except for Fzd10, the Figure 3. Regulation of the Fzd receptor genes in normal and fibrotic kidneys. (A) Representative RT-PCR results show the expression of different Fzd receptor genes in mouse kidney.
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