BRG1 regulates endothelial-derived IL-33 to promote ischemia-reperfusion induced renal injury and fibrosis in mice
BRG1 regulates endothelial-derived IL-33 to promote ischemia-reperfusion induced renal injury and fibrosis in mice
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BRG1调节内皮源性IL-33促进小鼠缺血再灌注肾损伤和纤维化
DOI：
10.1016/j.bbadis.2019.06.015
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发表时间：
2019-09-01
影响因子：
6.2
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Liu, Li;Mao, Lei;Xu, Yong
内皮衍生因子调节了广泛的病理生理事件。先前有报道称IL-33促进小鼠急性肾损伤（AKI），尽管其潜在的表观遗传机制尚不清楚。在本研究中，我们研究了BRG1（一种染色质重塑蛋白）在AKI中的作用，重点研究了其对内皮细胞中IL-33表达的调节。将Smarca4-flox小鼠与Cdh5-Cre小鼠杂交，实现BRG1的内皮特异性缺失。AKI是由单侧肾缺血再灌注引起的。与野生型（WT）相比，内皮条件BRG1敲除（CKO）小鼠可以保护其免受缺血再灌注诱导的AKI，这可以通过血浆肌酐水平降低、细胞和管状坏死减轻以及免疫浸润减少来证明。通过细胞外基质蛋白的表达水平、胶原组织的小天狼星红染色和肾羟脯氨酸水平的定量显示，CKO小鼠的肾纤维化程度较轻。有趣的是，内皮细胞BRG1缺乏导致IL-33在肾脏的表达下调。在培养的内皮细胞中，BRG1直接结合IL-33启动子激活转录。内皮细胞衍生的条件培养基促进肾小管上皮细胞中促纤维化蛋白的合成。内皮细胞中BRG1或IL-33的敲低均可减弱肾小管上皮细胞的促纤维化反应。总之，我们认为BRG1可能通过促进内皮细胞中IL-33的转录而参与缺血再灌注诱导的肾损伤和纤维化。
Endothelial-derived factors regulate a wide range of pathophysiological events. It has been reported previously that IL-33 promotes acute kidney injury (AKI) in mice although the underlying epigenetic mechanism is unclear. In the present study we investigated the role of BRG1, a chromatin remodeling protein, in AKI with a focus on its regulation of IL-33 expression in endothelial cells. Smarca4-flox mice were crossbred with Cdh5-Cre mice to achieve endothelial-specific deletion of BRG1. AKI was induced by unilateral renal ischemia followed by re perfusion. Compared to wild type (WT) littermates, endothelial conditional BRG1 knockout (CKO) mice were protected from ischemia-reperfusion induced AKI as evidenced by decreased plasma creatinine levels, attenuated caste and tubular necrosis, and diminished immune infiltrates. CKO mice also developed less severe renal fibrosis as indicated by expression levels of extracellular matrix proteins, picrosirius red staining of collagenous tissues, and quantification of renal hydroxylproline levels. Of interest, renal expression of IL-33 was down-regulated as result of endothelial BRG1 deficiency. In cultured endothelial cells, BRG1 directly bound to the IL-33 promoter to activate transcription. Endothelial cell-derived conditioned media promoted the synthesis of pro-fibrogenic proteins in renal tubular epithelial cells. Knockdown of either BRG1 or IL-33 in endothelial cells blunted the pro-fibrogenic response in renal tubular epithelial cells. In conclusion, we propose that BRG1 may contribute to ischemia-reperfusion induced renal injury and fibrosis by promoting IL-33 transcription in endothelial cells.