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Articles in PresS, published online ahead of print August 30, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.0009.2001
Submitted on January 12, 2001
Accepted on August 21, 2001
1 Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
* To whom correspondence should be addressed. E-mail: simon_t{at}kids.wustl.edu.
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 expression 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
a-smooth muscle actin. In support of a functional role for Wnt-4 in these activated
myofibroblasts, Wnt-4 induces stabilization of cytosolic ß-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.
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