Wnt/β-Catenin Signaling Modulates Survival of High Glucose–Stressed Mesangial Cells

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/␤-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.

Lithium in the Kidney: Friend and Foe?

“…Instead, several GSK3-specific inhibitors other than lithium, like TDZD-8 or BIO, mimicked the protective effects of lithium. 12,15,16,18,[87][88][89] Consistently, mice carrying an inactive GSK3b mutant were protected from mercuric chloride-induced nephrotoxic injury. 90 Therefore, we will focus on GSK3 as the target of lithium contributing to renoprotection with lithium ( Figure 2).…”

“…99,100 Different GSK3 inhibitors, including lithium, prevent ROS-induced apoptosis of mesangial cells and renal proximal epithelial cells. 87,[101][102][103] Although the molecular mechanism by which GSK3 inhibition prevents renal oxidative damage has not been investigated, studies on extrarenal tissues show that ROSinduced GSK3 activation induces the opening of the mitochondrial permeability transition pore, eventually resulting in cell death. 104,105 Active GSK3a/b induces permeability transition pore opening by activating Bax and BIM in the cytosol and cyclophilin-D in the mitochondrion (Figure 2, right panel).…”

Erythropoietin and Oxidative Stress

“…Wnt signaling also can inhibit apoptosis during oxidative stress (Chong and Maiese, 2004) and β-amyloid toxicity that may require modulation of glycogen synthase kinase-3β (GSK-3β) and β-catenin Lehman, et al, 2007, Scott, et al, 2006 as well as have increased association with obesity ). Yet, intact Wnt family members may offer glucose tolerance and increased insulin sensitivity as well as protect glomerular mesangial cells from elevated glucose induced apoptosis (Lin, et al, 2006). These observations suggest a potential protective cellular mechanism for EPO through Wnt signaling to improve clinical cardiac function in diabetic patients and decrease complications in woman with diabetic pregnancies (Teramo, et al, 2004).…”

“…Yet, intact Wnt family members may offer glucose tolerance and increased insulin sensitivity as well as protect glomerular mesangial cells from elevated glucose induced apoptosis (Lin, et al, 2006). These observations suggest a potential protective cellular mechanism for EPO through Wnt signaling to improve clinical cardiac function in diabetic patients and decrease complications in woman with diabetic pregnancies (Teramo, et al, 2004).…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…Experimental studies in mice that develop hyperglycemia through a high fat diet also demonstrate increased expression of some Wnt family members, such as Wnt3a and Wnt7a [194]. Yet, intact Wnt family members may offer glucose tolerance and increased insulin sensitivity [195] as well as protect glomerular mesangial cells from elevated glucose induced apoptosis [196]. Animals that over-expressed Wnt10b and were placed on a high-fat diet had a reduction in bodyweight, hyperinsulinemia, triglyceride plasma levels, and improved glucose homeostasis [197].…”