Simvastatin Reverses High Glucose-Induced Apoptosis of Mesangial Cells via Modulation of Wnt Signaling Pathway

Abstract

Background/Aims: Disruption of Wnt/β-catenin signaling in mesangial cells is a pathogenic consequence of diabetic nephropathy. We examined the role of simvastatin (SIM) in modulation of Wnt/β-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 β-catenin levels and phospho-Akt expression. This suggests that SIM alters the stability of β-catenin, a critical element of mesangial cell survival. Exogenous SIM treatment blocked DNA fragmentation, increased the Wnt/β-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/β-catenin signaling and thereby blocks mesangial cell apoptosis.

Yi Qi Qing Re Gao-containing serum inhibits lipopolysaccharide-induced rat mesangial cell proliferation by suppressing the Wnt pathway and TGF-β1 expression

“…In addition, transfection of MCs with Wnt4, Wnt5a or persistent activation of β-catenin, was able to inhibit high glucose-induced mesangial apoptosis. Furthermore, treatment with simvastatin restored Wnt4, Wnt5a and β-catenin expression in MCs and attenuated diabetic kidney injuries both in vivo and in vitro (16). In addition, it has been demonstrated that abrogation of oxidative stress may restore Wnt5a/β-catenin signaling and attenuate high glucose-induced MC apoptosis (25).…”

“…In podocyte injury and proteinuric kidney diseases, the Wnt pathways are essential regulators and potential therapeutic targets (13,14). Studies regarding the role of the Wnt signaling pathway in MCs have mainly focused on hyperglycemic conditions (15,16,25,26). Lin et al (15) observed that in diabetic nephropathy, the Wnt/β-catenin signaling pathway serves a crucial role in the regulation of MC proliferation.…”

“…Disassembly of the β-catenin destruction complex hinders the normal phosphorylation and ubiquitination process of cytoplasmic β-catenin, allowing it to accumulate in the cytosol and translocate into the nucleus, where it stimulates the transcription of its target genes, including Twist, Snail, fibronectin, and matrix metalloproteinase-7 (9). The Wnt pathway has previously been demonstrated to be involved in renal tubular atrophy and interstitial fibrosis of an obstructed renal model (10,11), podocyte apoptosis and dysfunction, albuminuria and slit diaphragm (12)(13)(14), and high glucose-induced MC apoptosis (15,16). Interactions between Wnt/β-catenin and TGF-β signaling pathways have been shown to be important in the pathogenesis of fibrosis (17,18).…”

Insulin attenuates apoptosis induced by high glucose via the PI3-kinase/Akt pathway in rat peritoneal mesothelial cells

“…PMCs are exposed to non-physiological doses of glucose in PD patients. Generally, PDFs contain high concentrations of glucose as an osmotic substance, and high glucose concentrations are known to influence cell survival, growth and apoptosis, and affect cell signaling pathways in several cell types [13,26]. Although the effects of high glucose concentrations on cell survival and morphological changes in PMCs have been reported [14], the molecular mechanisms and cell signaling pathways are unclear.…”

Renal function in a rat model of neurogenic bladder, effect of statins and phosphodiesterase-5 inhibitors

“…They also decrease renal inflammatory diseases through molecular pathways and declining oxidative stress [8] and the urinary stone formation [9]. They are introduced to improve the renal function particularly in spinal injuries to prevent urinary complication [10].…”