Wnt/beta-catenin signaling modulates survival of high glucose-stressed mesangial cells.
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/beta-catenin signaling in controlling high glucose-induced mesangial cell apoptosis is not well defined. Herein is reported that Wnt/beta-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 beta-catenin, whereas it increased glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activities and apoptosis of glomerular mesangial cells. Suppression of GSK-3beta activation or increase in nuclear beta-catenin by transfection of Wnt4 or Wnt5a or stable beta-catenin (S33Y) reversed Akt activation and reduced the high glucose-mediated caspase-3 cleavage and cell apoptosis. Pharmacologic inhibition of GSK-3beta by recombinant Wnt5a or bromoindirubin-3'-oxime or LiCl increased Akt phosphorylation and beta-catenin translocation and abrogated high glucose-mediated proapoptotic activities. Exogenous bromoindirubin-3'-oxime treatment reduced phospho-Ser(9)-GSK-3beta and beta-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/beta-catenin signaling is beneficial for promoting survival of mesangial cells that are exposed to high glucose stress.
Lin
Chun-Liang
CL
Department of Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung 833, Taiwan. linchunliang@adm.cgmh.org.tw
Wang
Jeng-Yi
JY
Huang
Yu-Ting
YT
Kuo
Yu-Hsia
YH
Surendran
Kameswaran
K
Wang
Feng-Sheng
FS
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000473:pathology; D005921:Glomerulonephritis / Q000209:etiology; D015433:Glomerulonephritis, Membranous / Q000209:etiology; D005947:Glucose / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C555583:Wnt4 protein, rat; C438615:Wnt5a protein, mouse; C491837:Wnt5a protein, rat; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D005947:Glucose