Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair.
Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair.
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DOI：
10.1038/s41467-022-34287-5
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发表时间：
2022-10-31
影响因子：
16.6
通讯作者：
Hou, Fan Fan
中科院分区：
文献类型：
--
作者：
Wang, Peng;Huang, Zhitao;Peng, Yili;Li, Hongwei;Lin, Tong;Zhao, Yingyu;Hu, Zheng;Zhou, Zhanmei;Zhou, Weijie;Liu, Youhua;Hou, Fan Fan
损伤后纤维化反应的机制尚不清楚。损伤后G2/M期上皮细胞周期停滞是决定创伤愈合是否导致正常细胞增殖或纤维化的关键检查点。在这里，我们发现了一种富含肾脏和肝脏的环状RNA，CircBNC2，在正常肾小管细胞和肝细胞中大量表达，但在急性缺血或中毒后显著下调。CircBNC2的缺失至少部分是通过DHX9的上调来调节的。体外和体内的功能获得和功能丧失研究表明，CircBNC2通过编码促进CDK1/Cyclin B1复合体形成的蛋白质，作为细胞G2/M停滞的负调控因子。在实验诱导的雄性小鼠肝肾纤维化模型中，恢复CircBNC2可减少G2/M期细胞数和纤维化因子的分泌，从而减轻细胞外基质沉积和纤维化。在人类缺血再灌注损伤(IRI)诱导的慢性肾脏疾病和炎症诱导的肝纤维化中，CircBNC2的表达减少和上皮细胞G2/M期停滞增加，强调了临床意义。这些发现表明，修复CircBNC2可能是一种潜在的治疗干预上皮器官纤维化的策略。上皮细胞G2/M期阻滞导致纤维化，其机制尚不清楚。本研究确定了一种编码蛋白的CircRNA，CircBNC2，它能抑制上皮细胞G2/M期停滞，以防止受损的肾脏和肝脏的纤维适应性不良修复，揭示了一个潜在的纤维化干预靶点。
The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis. G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis.
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影响因子：
14.9
作者：
Ma J;Chen T;Wu S;Yang C;Bai M;Shu K;Li K;Zhang G;Jin Z;He F;Hermjakob H;Zhu Y
通讯作者：
Zhu Y
DOI：
10.1097/01.asn.0000067652.51441.21
发表时间：
2003-06-01
影响因子：
13.6
作者：
Bonventre, JV
通讯作者：
Bonventre, JV
影响因子：
64.8
作者：
Aktas, Tugce;Ilik, Ibrahim Avsar;Akhtar, Asifa
通讯作者：
Akhtar, Asifa
影响因子：
16.6
作者：
Kristensen, Lasse S.;Ebbesen, Karoline K.;Hager, Henrik
通讯作者：
Hager, Henrik
靶向环状 RNA 作为治疗方法：当前策略和挑战。
影响因子：
39.3
作者：
He AT;Liu J;Li F;Yang BB
通讯作者：
Yang BB