RGD Reference Report - Wnt/beta-catenin signaling promotes renal interstitial fibrosis. - Rat Genome Database

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Wnt/beta-catenin signaling promotes renal interstitial fibrosis.

Authors: He, W  Dai, C  Li, Y  Zeng, G  Monga, SP  Liu, Y 
Citation: He W, etal., J Am Soc Nephrol. 2009 Apr;20(4):765-76. doi: 10.1681/ASN.2008060566. Epub 2009 Mar 18.
RGD ID: 7207450
Pubmed: PMID:19297557   (View Abstract at PubMed)
PMCID: PMC2663839   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2008060566   (Journal Full-text)

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 beta-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/beta-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal beta-catenin abundance. Delivery of the 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 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/beta-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
renal fibrosis  ISOMyc (Mus musculus)7207450; 7207450associated with Ureteral Obstruction and protein:increased expression:kidney (mouse)RGD 
renal fibrosis  IEP 7207450associated with Ureteral Obstruction and protein:increased expression:kidney (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Myc  (MYC proto-oncogene, bHLH transcription factor)

Genes (Mus musculus)
Myc  (myelocytomatosis oncogene)

Genes (Homo sapiens)
MYC  (MYC proto-oncogene, bHLH transcription factor)


Additional Information