Astaxanthin ameliorates experimental diabetes-induced renal oxidative stress and fibronectin by upregulating connexin43 in glomerular mesangial cells and diabetic mice
Astaxanthin ameliorates experimental diabetes-induced renal oxidative stress and fibronectin by upregulating connexin43 in glomerular mesangial cells and diabetic mice
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DOI：
10.1016/j.ejphar.2018.09.028
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发表时间：
2018-12-05
影响因子：
5
通讯作者：
Xie, Xi
中科院分区：
文献类型：
--
作者：
Chen, Qing;Tao, Jun;Xie, Xi
氧化应激是DN进展过程中肾纤维化的主要原因。连接蛋白43（Cx43）对糖尿病肾脏具有抗纤维化作用。本研究旨在探讨虾青素（astaxanthin，AST）是否能通过上调Cx43和激活Nrf 2/ARE信号通路，增强肾小球系膜细胞（GMCs）的抗氧化能力，减少纤维连接蛋白（fibronectin，FN）的积累，从而改善糖尿病肾病的病理进展。我们的假设在db/db小鼠的GMC和肾脏中通过western blot、免疫荧光、免疫组织化学、免疫沉淀、双荧光素酶报告基因分析和活性氧相关检测试剂盒得到验证。结果表明，AST可上调db/db小鼠和HG处理的GMCs肾脏Cx43蛋白水平，并促进Nrf 2/ARE信号通路活性。然而，Cx43缺失废除了由AST诱导的Nrf 2/ARE信号转导激活。AST降低高糖培养的GMC核内c-Src与Nrf 2的相互作用，从而促进Nrf 2在GMC核内的积聚。提示AST通过上调Cx43蛋白水平，促进Nrf 2/ARE信号通路，从而抑制高糖诱导的GMCs和db/db小鼠肾纤维化。c-Src在这些过程中起着介导作用。
Oxidative stress is the major cause of renal fibrosis in the progression of DN. Connexin43 (Cx43) exerts an antifibrosis effect on diabetic kidneys. The current study aimed to investigate whether astaxanthin (AST) could ameliorate the pathological progression of DN by upregulating Cx43 and activating the Nrf2/ARE signaling, which is a pivotal anti-oxidative stress system, to strengthen the cellular anti-oxidative capacity and diminish fibronectin (FN) accumulation in HG-induced glomerular mesangial cells (GMCs). Our hypothesis was verified in GMCs and the kidneys from db/db mice by western blot, immunofluorescence, immunohistochemistry, immunoprecipitation, dual luciferase reporter assay and reactive oxygen related detection kits. Results showed that AST simultaneously upregulated the Cx43 protein level and promoted the Nrf2/ARE signaling activity in the kidney of db/db mice and HG-treated GMCs. However, Cx43 depletion abrogated the Nrf2/ARE signaling activation induced by AST. AST reduced the interaction between c-Src and Nrf2 in the nuclei of GMCs cultured with HG, thereby enhancing the Nrf2 accumulation in the nuclei of GMCs. Our data suggested that AST promoted the Nrf2/ARE signaling by upregulating the Cx43 protein level to prevent renal fibrosis triggered by HG in GMCs and db/db mice. c-Src acted as a mediator in these processes.