Knockout of the Tachykinin Receptor 1 in the Mdr2−/− (Abcb4−/−) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis
Copyright policy )Knockout of the Tachykinin Receptor 1 in the Mdr2−/− (Abcb4−/−) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis
Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2-/- (alias Abcb4-/-) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R-/ (alias Tacr1-/-) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R-/-; (ii) Mdr2-/-; and (iii) NK1R-/-/Mdr2-/- (Tacr1-/-/Abcb4-/-) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R-/-/Mdr2-/- mice compared with Mdr2-/- mice. Elevated expression of miR-31 was observed in Mdr2-/- mice, which was reduced in NK1R-/-/Mdr2-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.
- University of Vermont Medical Center United States
- Roma Tre University Italy
- Indiana University United States
- DePaul University United States
- Texas A&M University United States
Liver Cirrhosis, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Sub-Family B Member 4, Cholangitis, Sclerosing, Receptors, Neurokinin-1, ATP binding cassette transporter; subfamily B; animals; disease models; gene knockdown techniques; mice; knockout; receptors; neurokinin-1; bile ducts; cholangitis; sclerosing; liver cirrhosis, Disease Models, Animal, Gene Knockdown Techniques, Liver cirrhosis, Neurokinin-1 receptors, Animals, Bile ducts, Bile Ducts, Sclerosing cholangitis
Liver Cirrhosis, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Sub-Family B Member 4, Cholangitis, Sclerosing, Receptors, Neurokinin-1, ATP binding cassette transporter; subfamily B; animals; disease models; gene knockdown techniques; mice; knockout; receptors; neurokinin-1; bile ducts; cholangitis; sclerosing; liver cirrhosis, Disease Models, Animal, Gene Knockdown Techniques, Liver cirrhosis, Neurokinin-1 receptors, Animals, Bile ducts, Bile Ducts, Sclerosing cholangitis
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