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Circular RNA circBNC2 regulates epithelial cell G2-M arrest to prevent fibrotic maladaptive repair

ABSTRACT: Epithelial cells arrested in G2/M phase of the cell cycle after injury is a key checkpoint for determining the wound-healing to either normal cell proliferation or fibrosis. The mechanism that regulates the fibrogenic response after injury is not well understood. Here, we identified a kidney- and liver-enriched circular RNA, circBNC2, which was abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insults. The loss of circBNC2 was at least partially mediated by upregulation of DHX9. Gain-of- and loss-of-function studies, both in vitro and in vivo, demonstrated that circBNC2 acted as a negative regulator for cell G2/M arrest by encoding a novel protein that promoted formation of CDK1/cyclin B1 complex. Restoring circBNC2 in experimentally-induced fibrotic kidney and liver decreased G2/M arrested cells with secretion of fibrotic factors, mitigated extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increasement of G2/M arrest of epithelial cells were recapitulated in human IRI-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that preventing the fibrogenic response by regulating cell cycle arrest might be a potential therapeutic strategy for organ fibrosis.

ORGANISM(S): Homo Sapiens

SUBMITTER: FanFan Hou

PROVIDER: PXD033284 | iProX | Mon Apr 18 00:00:00 BST 2022

REPOSITORIES: iProX

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Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair.

Wang Peng P Huang Zhitao Z Peng Yili Y Li Hongwei H Lin Tong T Zhao Yingyu Y Hu Zheng Z Zhou Zhanmei Z Zhou Weijie W Liu Youhua Y Hou Fan Fan FF

Nature communications 20221031 1

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 me ...[more]

PMID: 36316334

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Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.

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Circular RNA circBNC2 regulates epithelial cell G2-M arrest to prevent fibrotic maladaptive repair

Publications

Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair.

Similar Datasets

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