Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2551-2561. doi: 10.1016/j.bbadis.2019.06.015. Epub 2019 Jun 19.
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 reperfusion. 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.
内皮细胞衍生因子调节广泛的病理生理事件。先前有报道称，IL-33 可促进小鼠急性肾损伤（AKI），但其潜在的表观遗传机制尚不清楚。在本研究中，我们研究了染色质重塑蛋白 BRG1 在 AKI 中的作用，重点研究其对内皮细胞中 IL-33 表达的调节作用。Smarca4-flox 小鼠与 Cdh5-Cre 小鼠杂交，以实现内皮细胞特异性 BRG1 缺失。通过单侧肾缺血再灌注诱导 AKI。与野生型（WT）同窝仔相比，内皮条件性 BRG1 敲除（CKO）小鼠对缺血再灌注诱导的 AKI 具有保护作用，表现为血浆肌酐水平降低、铸型和肾小管坏死减轻以及免疫浸润减少。CKO 小鼠的肾脏纤维化也较轻，表现为细胞外基质蛋白的表达水平、胶原组织的苦味酸红染色和肾脏羟脯氨酸水平的定量降低。有趣的是，由于内皮 BRG1 缺失，肾脏中 IL-33 的表达下调。在培养的内皮细胞中，BRG1 直接与 IL-33 启动子结合以激活转录。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。在内皮细胞中敲低 BRG1 或 IL-33 可削弱肾小管上皮细胞中的促纤维化反应。总之，我们提出 BRG1 可能通过促进内皮细胞中 IL-33 的转录，导致缺血再灌注引起的肾脏损伤和纤维化。
