Wnt/β-Catenin Signaling Modulates Survival of High Glucose–Stressed Mesangial Cells
- 1 October 2006
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 17 (10), 2812-2820
- https://doi.org/10.1681/asn.2005121355
Abstract
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/β-catenin signaling in controlling high glucose–induced mesangial cell apoptosis is not well defined. Herein is reported that Wnt/β-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 β-catenin, whereas it increased glycogen synthase kinase-3β (GSK-3β) and caspase-3 activities and apoptosis of glomerular mesangial cells. Suppression of GSK-3β activation or increase in nuclear β-catenin by transfection of Wnt4 or Wnt5a or stable β-catenin (S33Y) reversed Akt activation and reduced the high glucose–mediated caspase-3 cleavage and cell apoptosis. Pharmacologic inhibition of GSK-3β by recombinant Wnt5a or bromoindirubin-3′-oxime or LiCl increased Akt phosphorylation and β-catenin translocation and abrogated high glucose–mediated proapoptotic activities. Exogenous bromoindirubin-3′-oxime treatment reduced phospho-Ser9-GSK-3β and β-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/β-catenin signaling is beneficial for promoting survival of mesangial cells that are exposed to high glucose stress.Keywords
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