Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy
Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy
复制标题
龙胆苦苷激活胆汁酸受体 Gpbar1 (TGR5)，抑制 NF-kappaB 通路并改善糖尿病肾病
DOI：
10.1016/j.phrs.2019.104559
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发表时间：
2020-01-01
影响因子：
9.3
通讯作者：
Huang, Heqing
中科院分区：
文献类型：
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作者：
Xiao, Haiming;Sun, Xiaohong;Huang, Heqing
我们以前的研究表明，G蛋白偶联的胆汁酸受体Gpbar1(TGR5)通过抑制NF-kappa B信号通路而抑制炎症，最终减轻糖尿病肾病(DN)。龙胆苦苷(Gentiopmicroside，GPS)是龙胆中主要的环烯醚萜糖苷类化合物，通过抑制炎症信号转导途径抑制多种疾病的炎症反应。然而，GPS是否通过激活TGR5抑制了核因子-kappaB信号通路，从而调节糖尿病肾纤维化的病理进展，还有待进一步研究。在本研究中，我们发现GPS能显著逆转高糖诱导的肾小球系膜细胞(GMCs)TGR5表达下调，抑制高糖诱导的肾小球系膜细胞(GMCs)纤维连接蛋白(FN)、转化生长因子β1(TGF-β1)、细胞间黏附分子-1(ICAM-1)和血管黏附分子-1(VCAM-1)的过度表达。此外，GPS还阻止了I-kappa Bα的磷酸化和降解，进而抑制了核因子-kappa B信号通路的激活。进一步的研究发现，GPS通过激活TGR5促进β-arrestin2与I kappa Bα的相互作用，从而增强了I kappa Bα的稳定性，从而抑制了NF-kappa B信号通路。重要的是，TGR5的缺失阻断了对NF-kappa B信号通路的抑制，并逆转了GPS对HG诱导的GMCs中FN、ICAM-1、VCAM-1和TGF-β1的下调。此外，GPS还可提高STZ糖尿病小鼠肾脏TGR5蛋白水平，促进Ikappa Bα与β-arrestin2之间的相互作用，从而抑制Ikappa Bα的减少，阻断肾组织中核转录因子-kappaBp65的核转位。综上所述，这些数据表明，GPS调节TGR5-β-arrestin2-NF-kappa B信号通路，以防止糖尿病小鼠肾脏炎症，并最终改善糖尿病肾纤维化的病理进展。
Our previous studies indicated that the G-protein-coupled bile acid receptor, Gpbar1 (TGR5), inhibits inflammation by inhibiting the NF-kappa B signalling pathway, eventually attenuating diabetic nephropathy (DN). Gentiopicroside (GPS), the main active secoiridoid glycoside of Gentiana manshurica Kitagawa, has been demonstrated to inhibit inflammation in various diseases via inhibiting the inflammatory signalling pathways. However, whether GPS inhibits the NF-kappa B signalling pathway by activating TGR5 and regulates the pathological progression of diabetic renal fibrosis requires further investigation. In this study, we found that GPS significantly reversed the downregulation of TGR5 and inhibited the overproduction of fibronectin (FN), transforming growth factor beta 1 (TGF-beta 1), intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMCs) exposed to high glucose (HG). Additionally, GPS prevented the phosphorylation and degradation of I kappa B alpha, and subsequently inhibited the activation of the NF-kappa B signalling pathway. Further investigation found that GPS enhanced the stabilization of I kappa B alpha by promoting the interaction of beta-arrestin2 with I kappa B alpha via TGR5 activation, which contributed to the inhibition of NF-kappa B signalling pathway. Importantly, the depletion of TGR5 blocked the inhibition of the NF-kappa B signalling pathway and reversed the downregulation of FN, ICAM-1, VCAM-1 and TGF-beta 1 by GPS in HG-induced GMCs. Moreover, GPS increased the TGR5 protein levels and promoted the interaction between I kappa B alpha and beta-arrestin2, thereby inhibiting the reduction of I kappa B alpha and blocked NF-kappa B p65 nuclear translocation in the kidneys of STZ-induced diabetic mice. Collectively, these data suggested that GPS regulates the TGR5-beta-arrestin2-NF-kappa B signalling pathway to prevent inflammation in the kidneys of diabetic mice, and ultimately ameliorates the pathological progression of diabetic renal fibrosis.