Abstract
Oxidative stress is the main cause of diabetic nephropathy (DN) progression. Nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling is a crucial cellular defense system to cope with oxidative stress. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid with remarkable antioxidative capacity. AST exerted renal protective in diabetic rats. This study aimed to determine whether AST could alleviate the pathological progress of DN by activating Nrf2/ARE signaling and diminishing the excessive oxidative stress and fibronectin (FN) accumulation in glomerular mesangial cells (GMCs) challenged with high glucose (HG). In the current study, we found that AST treatment alleviated the metabolic parameters, renal morphology and extracellular matrix (ECM) accumulation in streptozotocin-induced diabetic rats. Additionally, HG induced the adaptively activated Nrf2/ARE signaling and increased the expression of FN, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-β1 (TGF-β1), as well as the intracellular reactive oxygen species (ROS) generation in GMCs. However, AST treatment strongly promoted the nuclear translocation and transcriptional activity of Nrf2 as well as upregulated the expression of superoxide dismutase (SOD1), NAD(P)H: quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1), ultimately quenching the higher level of ROS and inhibiting the FN, ICAM-1 and TGF-β1 expression induced by HG. Collectively, our data suggest that the renoprotective effect of AST on DN depends on Nrf2/ARE signaling activation, which could be a potentially therapeutic strategy in the treatment of DN.
Highlights
Diabetic nephropathy (DN) is a severe microvascular complication of diabetes that is characterized by sequential pathology, including renal hypertrophy and basement membrane thickening at the early stages and extracellular matrix (ECM) (such as fibronectin (FN) and collagen accumulation), glomerulosclerosis, and interstitial fibrosis at the latter stages, leading to renal function loss and end-stage renal diseases [1,2]
12 weeks of therapy with AST (25 mg/kg daily i.g.), the diabetic rats exhibited a significant reduction in these parameters except blood glucose (p < 0.05; Table 1)
SOD1, NQO1 and heme oxygenase-1 (HO-1), quenching the higher level of reactive oxygen species (ROS) and inhibiting the FN, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-β1 (TGF-β1) expression induced by high glucose (HG)
Summary
Diabetic nephropathy (DN) is a severe microvascular complication of diabetes that is characterized by sequential pathology, including renal hypertrophy and basement membrane thickening at the early stages and extracellular matrix (ECM) (such as fibronectin (FN) and collagen accumulation), glomerulosclerosis, and interstitial fibrosis at the latter stages, leading to renal function loss and end-stage renal diseases [1,2].Glomerular mesangial cells (GMCs) play important roles in the physiological and pathological processes of kidneys. Diabetic nephropathy (DN) is a severe microvascular complication of diabetes that is characterized by sequential pathology, including renal hypertrophy and basement membrane thickening at the early stages and extracellular matrix (ECM) (such as fibronectin (FN) and collagen accumulation), glomerulosclerosis, and interstitial fibrosis at the latter stages, leading to renal function loss and end-stage renal diseases [1,2]. GMCs generate ECM, intercellular adhesion molecule-1 (ICAM-1) and. Mar. Drugs 2018, 16, 117 transforming growth factor-β1 (TGF-β1), which trigger the thickening of the glomerular and tubular basement membranes. Drugs 2018, 16, 117 transforming growth factor-β1 (TGF-β1), which trigger the thickening of the glomerular and tubular basement membranes This phenomenon accelerates the pathological processes of glomerulosclerosis and tubulointerstitial fibrosis, leading to DN [3,4]. Inhibiting FN in GMC production is an effective strategy for ameliorating DN
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