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钙/P53/Ninjurin 1 信号转导介导重症急性胰腺炎腺泡细胞的质膜破裂。

Calcium/P53/Ninjurin 1 Signaling Mediates Plasma Membrane Rupture of Acinar Cells in Severe Acute Pancreatitis.

机构信息

Department of Emergency Medicine and Laboratory of Ethnopharmacology, Tissue-Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.

出版信息

Int J Mol Sci. 2023 Jul 17;24(14):11554. doi: 10.3390/ijms241411554.

DOI:10.3390/ijms241411554
PMID:37511311
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10380776/
Abstract

Ninjurin 1 (NINJ1) is a double-transmembrane cell-surface protein that might mediate plasma membrane rupture (PMR) and the diffusion of inflammatory factors. PMR is a characteristic of acinar cell injury in severe acute pancreatitis (SAP). However, the involvement of NINJ1 in mediating the PMR of acinar cells in SAP is currently unclear. Our study has shown that NINJ1 is expressed in acinar cells, and the expression is significantly upregulated in sodium-taurocholate-induced SAP. The knockout of NINJ1 delays PMR in acinar cells and alleviates SAP. Moreover, we observed that NINJ1 expression is mediated by Ca concentration in acinar cells. Importantly, we found that Ca overload drives mitochondrial stress to upregulate the P53/NINJ1 pathway, inducing PMR in acinar cells, and amlodipine, a Ca channel inhibitor, can reduce the occurrence of PMR by decreasing the concentration of Ca. Our results demonstrate the mechanism by which NINJ1 induces PMR in SAP acinar cells and provide a potential new target for treatment of SAP.

摘要

Ninjurin 1（NINJ1）是一种双跨膜细胞表面蛋白，可能介导质膜破裂（PMR）和炎症因子的扩散。PMR 是重症急性胰腺炎（SAP）中腺泡细胞损伤的特征。然而，NINJ1 参与介导 SAP 中腺泡细胞的 PMR 目前尚不清楚。我们的研究表明，NINJ1 在腺泡细胞中表达，并且在牛磺胆酸钠诱导的 SAP 中表达显著上调。NINJ1 的敲除延迟了腺泡细胞的 PMR 并减轻了 SAP。此外，我们观察到 NINJ1 的表达是由腺泡细胞中的 Ca 浓度介导的。重要的是，我们发现 Ca 过载会导致线粒体应激，从而上调 P53/NINJ1 通路，诱导腺泡细胞的 PMR，而钙通道抑制剂氨氯地平可以通过降低 Ca 浓度来减少 PMR 的发生。我们的结果表明了 NINJ1 在 SAP 腺泡细胞中诱导 PMR 的机制，并为 SAP 的治疗提供了一个潜在的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d53/10380776/f0c3b105a76e/ijms-24-11554-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d53/10380776/f0c3b105a76e/ijms-24-11554-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d53/10380776/084f2c2de41b/ijms-24-11554-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d53/10380776/cfaec042efea/ijms-24-11554-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d53/10380776/2e88021fdfcd/ijms-24-11554-g003.jpg
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