Disruption of Small GTPase Rab7 Exacerbates the Severity of Acute Pancreatitis in Experimental Mouse Models.
Disruption of Small GTPase Rab7 Exacerbates the Severity of Acute Pancreatitis in Experimental Mouse Models.
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DOI：
10.1038/s41598-017-02988-3
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发表时间：
2017-06-06
影响因子：
4.6
通讯作者：
Ohnishi H
中科院分区：
文献类型：
--
作者：
Takahashi K;Mashima H;Miura K;Maeda D;Goto A;Goto T;Sun-Wada GH;Wada Y;Ohnishi H
虽然细胞内囊泡转运系统向溶酶体的畸变包括自噬和内吞作用参与了急性胰腺炎的发生和发展，但这些畸变的分子机制仍不清楚。自噬和内吞作用的途径密切相关，Rab 7在两者中起着关键作用。在这项研究中，我们分析了Rab 7在急性胰腺炎中的功能，使用胰腺特异性Rab 7敲除（Rab 7 Δpan）小鼠。Rab 7 Δpan胰腺腺泡细胞内体和自噬体的成熟过程均受到影响，溶酶体功能受到影响。在实验性急性胰腺炎模型中，Rab 7 Δpan小鼠的组织病理学严重程度、血清淀粉酶浓度和胰腺内胰蛋白酶活性显著高于野生型小鼠。此外，与野生型小鼠相比，Rab 7 Δpan胰腺中的自噬过程被阻断。此外，Rab 7 Δ泛胰腺腺泡细胞中更频繁地形成与早期内体抗原1（EEA 1）共定位而不与溶酶体相关膜蛋白（LAMP）-1共定位的较大自噬空泡。因此，Rab 7缺陷通过损害朝向溶酶体的自噬和内吞途径而加剧急性胰腺炎的严重性。
Although aberrations of intracellular vesicle transport systems towards lysosomes including autophagy and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7Δpan) mice. In Rab7Δpan pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7Δpan mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7Δpan pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7Δpan pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes.