Abstract
BackgroundHyperglycemia-induced advanced glycation end products (AGEs) and receptor for AGEs (RAGE) production play major roles in progression of diabetic nephropathy. Anti-RAGE effect of peroxisome proliferator-activated receptor-delta (PPARδ) agonists was shown in previous studies. PPARδ agonists also stimulate glucagon-like peptide-1 (GLP-1) secretion from human intestinal cells.MethodsIn this study, the individual and synergic anti-inflammatory effects of GLP-1 receptor (exendin-4) and PPARδ (L-165,041) agonists in AGE-treated rat mesangial cells (RMC) were investigated.ResultsThe results showed both exendin-4 and L-165,041 significantly attenuated AGE-induced IL-6 and TNF-α production, RAGE expression, and cell death in RMC. Similar anti-inflammatory potency was seen between 0.3 nM exendin-4 and 1 μM L-165,041. Synergic effect of exendin-4 and L-165,041 was shown in inhibiting cytokines production, but not in inhibiting RAGE expression or cell death.ConclusionsThese results suggest that both GLP-1 receptor and PPARδ agonists have anti-inflammatory effect on AGE-treated rat mesangial cells.
Highlights
Hyperglycemia-induced advanced glycation end products (AGEs) and receptor for AGEs (RAGE) production play major roles in progression of diabetic nephropathy
The AGE-induced IL-6 production was inhibited by the Peroxisome proliferator-activated receptor-delta (PPARδ) agonist, L-165,041, with a dose-dependent manner (Fig.1b)
We examined the effect of PPARδ and glucagon-like peptide-1 (GLP-1) receptor agonists against AGE-induced RAGE upregulation
Summary
Hyperglycemia-induced advanced glycation end products (AGEs) and receptor for AGEs (RAGE) production play major roles in progression of diabetic nephropathy. Anti-RAGE effect of peroxisome proliferator-activated receptor-delta (PPARδ) agonists was shown in previous studies. Large clinical trials revealed that strict control of blood glucose significantly reduced the development and progression of diabetic nephropathy in both type 1 and type 2 diabetes [2]. High serum glucose levels in diabetic patients stimulate the production of advanced glycation end products (AGEs), the transmembranous receptor for AGEs (RAGE), and various RAGE ligands in kidney cells. Ligand-induced activation of RAGE triggers numerous different signaling pathways, enhances oxidative. The peroxisome proliferator-activated receptor superfamily (PPARs) comprises a class of nuclear receptors with significant effects in regulating multiple cellular pathways. PPAR agonists are widely used in clinical therapy to enhance serum glucose control.
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