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Departments of 1 Pediatrics and 3 Molecular Biology and Pharmacology and 2 Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri 63110
Wnt-4 is a secreted glycoprotein
that is critical for genitourinary development but found only in the
most distal collecting duct epithelium in the normal murine adult
kidney. Wnt4 expression is induced throughout the collecting
ducts in four murine models of renal injury that produce
tubulointerstitial fibrosis: folic acid-induced nephropathy, unilateral
ureteral obstruction, renal needle puncture, and genetic polycystic
kidney disease. Wnt4 activation induced by injury is limited
to collecting ducts, with initial activation in the collecting duct
epithelium followed by activation in fibrotic lesions surrounding the
collecting ducts. The highest cellular Wnt4 expression is in
interstitial fibroblasts in the fibrotic lesions that also express high
levels of collagen-
1(I) mRNA and -smooth muscle actin. In support
of a functional role for Wnt-4 in these activated myofibroblasts, Wnt-4
induces stabilization of cytosolic 
-catenin in a cultured
myofibroblast cell line. Furthermore, Wnt-4-producing fibroblasts
placed under the renal capsule of adult mice induce lesions with
tubular epithelial destruction. These observations suggest a role for
Wnt-4 in the pathogenesis of renal fibrosis.
tubulointerstitial disease; interstitial fibroblast; -catenin; kidney
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