Simvastatin reverses high glucose-induced apoptosis of mesangial cells via modulation of Wnt signaling pathway.
OBJECTIVE
Disruption of Wnt/beta-catenin signaling in mesangial cells is a pathogenic consequence of diabetic nephropathy. We examined the role of simvastatin (SIM) in modulation of Wnt/beta-catenin signaling in the apoptosis of high glucose (HG)-stressed mesangial cells in vitro and in vivo.


METHODS
For in vitro studies, we cultured mesangial cells, with or without SIM pretreatment, in 35 mM glucose and then assayed Wnt activity and apoptosis. For in vivo studies, we administered SIM to streptozocin-induced diabetic rats for 28 days and then dissected renal tissues for immunohistological assessment of Wnt signal expression and apoptosis of glomerular cells.


RESULTS
SIM reduced the promotional effect of HG on caspase-3 expression, PARP activation, and cell apoptosis. HG significantly reduced Wnt4 and Wnt5a mRNA expression and SIM restored Wnt4 and Wnt5a mRNA expression to the level of controls. SIM also suppressed HG-mediated activation of GSK-3b and restored nuclear beta-catenin levels and phospho-Akt expression. This suggests that SIM alters the stability of beta-catenin, a critical element of mesangial cell survival. Exogenous SIM treatment blocked DNA fragmentation, increased the Wnt/beta-catenin immunoreactivities of cells adjacent to renal glomeruli, and attenuated urinary protein secretion in diabetic rats.


CONCLUSIONS
SIM reduces the detrimental effects of HG on diabetic renal glomeruli in vitro and in vivo. SIM prevents HG-induced downregulation of Wnt/beta-catenin signaling and thereby blocks mesangial cell apoptosis.
Lin
Chun-Liang
CL
Division of Nephrology, Chiayi Chang Gung Memorial Hospital and Graduate Institute of Clinical Medicine, Chang Gung University, Chiayi, Taiwan. linchunliang@adm.cgmh.org.tw
Cheng
Ho
H
Tung
Chun-Wu
CW
Huang
Wei-Jan
WJ
Chang
Pey-Jium
PJ
Yang
Jen-Tsung
JT
Wang
Jeng-Yi
JY
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D004789:Enzyme Activation; D005947:Glucose / Q000009:adverse effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D050527:Mesangial Cells / Q000166:cytology* / Q000473:pathology; D008954:Models, Biological; D051381:Rats; D015398:Signal Transduction; D019821:Simvastatin / Q000627:therapeutic use*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; D019821:Simvastatin; D053148:Caspase 3; D005947:Glucose