Exendin-4 Alleviates High Glucose-Induced Rat Mesangial Cell Dysfunction through the AMPK Pathway

Abstract

Background/Aims: Glucagon-like peptide-1 (GLP-1), which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin. Methods: Rat mesangial cells (MCs) were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK) inhibitors (compound C) and agonists (AICAR) were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinases (TIMP)-2 was evaluated using quantitative real-time RT-PCR. Results: Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK) phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR) in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C. Conclusion: Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.

Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model

“…OGD can induce oxidative stress, inflammatory cytokine accumulation, and MMP dissipation via NF-κB and ERK1/2 pathways in primary rat astrocytes. HG can result in the over-production of ROS and a loss of MMP [41][42][43]. Indeed, the results of this study showed that gp91phox is the common denominator in both processes.…”

Transcription Factor Egr1 is Involved in High Glucose-Induced Proliferation and Fibrosis in Rat Glomerular Mesangial Cells

“…Diabetic nephropathy is also associated with elevated type IV collagen in the urine [17] and increased secretion of fibronectin [18], but whether Egr1 up-regulates the expression of fibronectin and type IV collagen in MCs has not been directly demonstrated. Transfection of cultured MCs with a plasmid encoding Egr1 (M61-Egr1) increased the expression of Egr1 ▲▲ P < 0.01 vs. the empty vector group; ◆◆ P < 0.01 vs. M61-Egr1 group.…”

“…Since high glucose [18] as well as Egr1 [5,6] can promote MC proliferation, we hypothesized that Egr1 mediates high glucose-induced MC proliferation. To test this idea, we examined the effects of siEgr1 transfection on MC proliferation under high glucose conditions using the CCK-8 assays.…”

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells

“…Mesangial cell (MC) proliferation and extracellular matrix expansion play a pivotal role in the pathogenesis of glomerulosclerosis. A variety of signaling molecules are involved in proliferation and extracellular matrix expansion of MCs [6,7,8,9]. However, there have been relatively few studies to investigate the role of sympathetic hyperactivity in MCs.…”