Glomerulosclerosis and diabetic nephropathy are attributable to high glucose induction of mesangial cell apoptosis. Whereas Wnt signaling has been found to regulate renal morphogenesis and pathogenesis, the biologic role of Wnt/-catenin signaling in controlling high glucose-induced mesangial cell apoptosis is not well defined. Herein is reported that Wnt/-catenin signaling is required for protecting glomerular mesangial cells from high glucose-mediated cell apoptosis. High glucose downregulated Wnt4 and Wnt5a expression and the subsequent nuclear translocation of -catenin, whereas it increased glycogen synthase kinase-3 (GSK-3) and caspase-3 activities and apoptosis of glomerular mesangial cells. Suppression of GSK-3 activation or increase in nuclear -catenin by transfection of Wnt4 or Wnt5a or stable -catenin (S33Y) reversed Akt activation and reduced the high glucose-mediated caspase-3 cleavage and cell apoptosis. Pharmacologic inhibition of GSK-3 by recombinant Wnt5a or bromoindirubin-3-oxime or LiCl increased Akt phosphorylation and -catenin translocation and abrogated high glucose-mediated proapoptotic activities. Exogenous bromoindirubin-3-oxime treatment reduced phosphoSer 9 -GSK-3 and -catenin expression and apoptosis of cells adjacent to glomeruli in diabetic kidneys and attenuated urinary protein secretion in diabetic rats. Taken together, mesangial cells responded to high glucose by impairing that canonical Wnt pathway to increase proapoptotic activities. Sustaining Wnt/-catenin signaling is beneficial for promoting survival of mesangial cells that are exposed to high glucose stress.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.