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Disruption of Small GTPase Rab7 Exacerbates the Severity of Acute Pancreatitis in Experimental Mouse Models
Kenichi Takahashi1, Hirosato Mashima2, Kouichi Miura1
1Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita, Japan.
Abstract:
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.
Insights
Rab7 protein deficiency worsens acute pancreatitis by disrupting cellular waste removal pathways. Impaired autophagy and endocytosis in Rab7-deficient mice lead to increased disease severity and pancreatic damage.
Area of Science:
- Cell Biology
- Gastroenterology
- Molecular Medicine
Background:
- Aberrations in lysosomal pathways, including autophagy and endocytosis, are implicated in acute pancreatitis.
- The precise molecular mechanisms driving these cellular transport defects in pancreatitis are not fully understood.
- Rab7 is a key protein involved in both autophagy and endocytosis pathways.
Purpose of the Study:
- To investigate the role of Rab7 in the pathogenesis of acute pancreatitis.
- To elucidate how Rab7 deficiency affects pancreatic acinar cell function and lysosomal pathways.
Main Methods:
- Utilized pancreas-specific Rab7 knockout (Rab7Δpan) mice and wild-type littermates.
- Analyzed pancreatic acinar cell morphology, endosome and autophagosome maturation, and lysosomal function.
- Assessed histopathological severity, serum amylase levels, and intra-pancreatic trypsin activity in experimental acute pancreatitis models.
Main Results:
- Rab7Δpan mice exhibited impaired maturation of endosomes and autophagosomes, alongside compromised lysosomal function.
- Pancreatitis severity, serum amylase, and trypsin activity were significantly elevated in Rab7Δpan mice compared to controls.
- Autophagy was blocked in Rab7Δpan pancreata, with increased formation of enlarged autophagic vacuoles colocalizing with EEA1 but not LAMP-1.
Conclusions:
- Rab7 deficiency exacerbates acute pancreatitis.
- Impairment of autophagic and endocytic pathways towards lysosomes is the mechanism by which Rab7 deficiency worsens pancreatitis.
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01:27Acute Pancreatitis I: Introduction
Acute pancreatitis is characterized by rapid inflammation of the pancreas, often caused by factors like gallstone blockage or excessive alcohol consumption. Chronic pancreatitis, on the other hand, is a slow, progressive inflammation that may result from long-term alcohol abuse, obstructions in the pancreatic duct, or genetic factors.
The causes of acute pancreatitis include:
01:24Chronic Pancreatitis I: Introduction
Pancreatitis is the inflammation of the pancreas, which occurs when the immune system becomes active and causes swelling, pain, and disruptions in organ function. Pancreatitis can manifest as either an acute or chronic condition.
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