A role for Wnt-4 in renal fibrosis

Abstract

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-α1(I) mRNA and α-smooth muscle actin. In support of a functional role for Wnt-4 in these activated myofibroblasts, Wnt-4 induces stabilization of cytosolic β-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.

Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

“…Recent evidence has identified ␤-catenin, a powerful regulator of cell proliferation, as a key effector in fibrosis of both pulmonary and extrapulmonary organs. 41 Chilosi et al 18 reported evidence of aberrant Wnt/ ␤-catenin activation in fibroproliferative bronchiolar lesions and also nuclear ␤-catenin accumulation in the fibroblastic foci in lung samples from patients with IPF. More recently, Konigshoff et al 30 reported that WISP1, a target gene of the Wnt/␤-catenin pathway, is a key regulator of pulmonary fibrosis through its ability to induce collagen matrix deposition by fibroblasts and EMT.…”

Expression and Function of the Developmental Gene Wnt-4 during Experimental Acute Renal Failure in Rats

“…Surendran et al (34) recently observed low levels of Wnt-4 mRNA in the normal adult mouse kidney and that high levels of Wnt-4 expression induced in the collecting ducts in murine models of renal injury that produced tubulointerstitial fibrosis. In the ischemia/reperfusion model in our study, we did not observe a fibrotic area in the proximal tubules.…”

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

“…The folic acid (FA)-induced renal injury model has been applied recently for evaluation of epithelial regeneration and interstitial fibrosis. [21][22][23][24] Intraperitoneal administration of FA with sodium bicarbonate induced renal injury that showed acute tubular necrosis with transient elevations of blood urea nitrogen (BUN) and serum creatinine (Cr) followed by development of interstitial fibrosis with macrophage infiltration. 21,25 Tubular obstructions by FA crystals and direct toxic effect of FA to tubular epithelial cells presumably cause renal damage, 26 but the precise mechanism of injury remains unclear.…”