Astaxanthin protects against renal fibrosis through inhibiting myofibroblast activation and promoting CD8+ T cell recruitment
Astaxanthin protects against renal fibrosis through inhibiting myofibroblast activation and promoting CD8+ T cell recruitment
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虾青素通过抑制肌成纤维细胞活化和促进 CD8 T 细胞募集来预防肾纤维化
DOI：
10.1016/j.bbagen.2019.05.020
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发表时间：
2019-09-01
影响因子：
3
通讯作者：
Zhao, Xiaozhi
中科院分区：
文献类型：
--
作者：
Diao, Wenli;Chen, Wei A.;Zhao, Xiaozhi
背景：肾脏纤维化是慢性肾脏疾病常见的病理特征，临床上尚无有效的治疗方法来控制其进展。近年来，虾青素被发现具有抗纤维化作用，但其对肾脏纤维化的作用尚不清楚。方法：C57BL/6J小鼠单侧输尿管梗阻后给予虾青素灌胃。采用组织病理学和免疫组织化学方法评价肾纤维化程度。用流式细胞仪检测纤维化肾脏中淋巴细胞的积聚。通过Western blotting、实时荧光定量聚合酶链式反应和免疫荧光等方法研究虾青素在肾纤维化过程中的作用机制。结果：口服虾青素可有效减轻小鼠肾脏纤维化。在体外，虾青素通过调节Smad2、Akt和STAT3通路抑制成纤维细胞的激活，并通过Smad2、Snail和β-catenin抑制肾小管上皮细胞向间质的转化。此外，虾青素显著诱导CD8(+)T细胞在纤维化肾组织中快速积聚，并伴随着干扰素-γ的表达升高。因此，CD8(+)T细胞的耗尽大大减弱了虾青素的保护作用。进一步的研究表明，虾青素通过上调巨噬细胞中CCLS的表达来增加CD8(+)T细胞的数量。结论：这些结果突出了虾青素在肾纤维化过程中对成纤维细胞激活、上皮向间充质转化以及CD8(+)T细胞募集的有利作用。
Background: Renal fibrosis is a common pathological hallmark of chronic kidney disease, and no effective treatment is clinically available to manage its progression. Astaxanthin was recently found to be anti-fibrotic, but its effect on renal fibrosis remains unclear.Methods: C57BL/6J mice were subjected to unilateral ureteral obstruction and intragastrically administered astaxanthin. Histopathology and immunohistochemistry were performed to evaluate renal fibrosis. Flow cytometry was used to examine lymphocyte accumulation in the fibrotic kidneys. Western blotting, real-time qPCR, and immunofluorescence were performed to cover the underlying mechanism concerning astaxanthin treatment during renal fibrosis.Results: Oral administration of astaxanthin effectively alleviates renal fibrosis in mice. In vitro, astaxanthin inhibited fibroblast activation by modulating Smad2, Akt and STAT3 pathways and suppressed epithelial-to-mesenchymal transition in renal tubular epithelial cells through Smad2, snail, and beta-catenin. Moreover, astaxanthin significantly induced the rapid accumulation of CD8(+) T cells in fibrotic kidneys, which was accompanied by elevated expression of IFN-gamma. Accordingly, the depletion of CD8(+) T cells strongly diminished the protective effect of astaxanthin. Further investigation showed that astaxanthin increased the population of CD8(+) T cells by upregulating the expression of CCLS in macrophages.Conclusions: These findings highlight the beneficial effect of astaxanthin on fibroblast activation, epithelial-to-mesenchymal transition, and CD8(+) T cell recruitment during renal fibrosis.General significance: These data indicate that astaxanthin could serve as a therapeutic strategy to treat renal fibrotic conditions.