ABSTRACT
Chronic pancreatitis is a long-term inflammatory disease that results in irreversible scarring and a reduction in pancreatic function. This disease has multifactorial origins, involving both behavioral risks like diet, alcohol, and smoking, as well as genetic predispositions. One gene that has been implicated is CLDN2, which encodes claudin-2, a paracellular cation-selective channel localized at tight junctions. However, if and how claudin-2 may modify pancreatitis susceptibility have not been explored. We aimed to clarify the potential role of claudin-2 in the onset and progression of pancreatitis.
We employed multiple methodologies, including examining human pancreatic tissue, using the caerulein-induced experimental pancreatitis model, along with normal pancreatic ductal epithelial cell based organoid transport studies. In both human chronic pancreatitis tissues and in caerulein-induced experimental pancreatitis model, claudin-2 protein is significantly upregulated in pancreatic ductal epithelial cells. Genetically modified mice that lack claudin-2 expression develop more severe experimental pancreatitis, indicating claudin-2 plays a protective role in pancreatitis development. Our organoid based studies further demonstrate claudin-2 is critical for both sodium-dependent water transport and cAMP-dependent fluid secretion in pancreatic ductal epithelium. These findings suggest that intact claudin-2 function is essential for homeostatic and induced fluid transport, which could reduce pancreatitis severity by affecting pancreatic ductal secretion.
In conclusion, our studies suggest claudin-2 upregulation during pancreatitis may play a protective role for disease development and decreased claudin-2 function may increase pancreatitis severity. This points to the possibility of modulating pancreatic ductal claudin-2 function as an approach for pancreatitis therapy.
Competing Interest Statement
The authors have declared no competing interest.
