抄録
Background: Activation of Sirt1 and Nrf2/ARE, anti-oxidative stress signaling pathways, may play important regulatory roles in the pathogenesis of diabetic nephropathy (DN). Paeonol (PA), a small molecule phenolic compound with antioxidant capacity, has recently been demonstrated to have potential renoprotective effects on experimental diabetes. However, the exact regulatory effect of PA on inflammatory lesions of glomerular mesangial cells (GMCs) in diabetic kidneys and the mechanism of its anti-oxidation needs to be further elucidated. In this study, we explored whether PA could ameliorate high glucose (HG)-induced overproduction of fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1) by promoting the activation of Sirt1 and Nrf2/ARE signaling pathways.
Methods: Western blotting (WB), electrophoretic mobility shift assay (EMSA) and immunoprecipitation (IP) were performed to observed the effects of PA on HG-induced expressions of FN, ICAM-1 and Sirt1 as well as the nuclear content and DNA-binding activity of Nrf2 and expressions of its downstream target proteins HO-1 and SOD1.
Results: In HG-treated GMCs, PA upregulated the expression of Sirt1 and repressed the protein levels of FN and ICAM-1. Besides, PA increased the nuclear content and DNA-binding activity of Nrf2 as well as expressions of its downstream target proteins HO-1 and SOD1. Once Sirt1 or Nrf2 was depleted, the inhibitory effects of PA on FN and ICAM-1 expressions disappeared. Furthermore, PA enhanced the interaction between Sirt1 and Nrf2. Also in vivo, we found PA markedly enhanced Sirt1 and Nrf2 expressions in kidneys of diabetic mice and eventually repressed the up-regulation of FN and ICAM-1 expressions, thereby preventing the progression of diabetic renal fibrosis.
Conclusion: In a word, our study shows that PA promotes the Nrf2/ARE anti-oxidative pathway by up-regulating Sirt1 expression, thereby preventing diabetic renal fibrosis.
