1 research outputs found
The secretin receptor antagonist (SCT 5-27) reduces biliary hyperplasia and liver fibrosis in an animal model of primary sclerosing cholangitis
Secretin (SCT) is trophic and profibrotic hormone produced
by the S cells of the duodenum as well as cholangiocytes.
The SCT/secretin receptor (SR) axis stimulates biliary proliferation
in normal and cholestatic mice following bile duct ligation
(BDL). We have shown that SCT down-regulates the expression
of the miRNAs, miR-125b and let-7a, which target the expression
of VEGF-A and NGF, respectively, that are proliferative
factors that stimulate biliary proliferation during cholestasis.
The AIM of our study was to evaluate the effect of inhibition
of the SCT/SR axis with Sec 5-27 on biliary proliferation and
liver fibrosis in the Mdr2-/- mouse model of primary sclerosing
cholangitis (PSC). PSC is a disease characterized by inflammation
of cholangiocytes that leads to scar formation and duct
obstruction with subsequent cirrhosis and liver failure. Methods:
Our studies were performed in: (i) wild-type (WT) mice; and (ii)
12-wk old Mdr2-/- mice treated with saline or SCT 5-27 (10
μg/kg WT/day) by osmotic minipumps for 1 wk. Then, biliary
proliferation and intrahepatic bile duct mass (IBDM) were evaluated
by immunohistochemistry for PCNA and CK-19, respectively.
Liver fibrosis was determined by: (i) Sirius red staining
in liver sections; and (ii) qPCR for the profibrotic markers collagen
1, fibronectin, TGFβ1, alpha-SMA, MMP2, MMP9, TIMP-
1, TIMP-2 in total liver and purified cholangiocytes from the
in vivo treatment groups. The expression levels of miR-125b,
let-7a, VEGF-A and NGF in total liver and cholangiocytes
were evaluated by qPCR. The serum levels of transaminases
were evaluated. Serum and cholangiocyte supernatant levels
of TGFβ1 (a key factor for the activation of hepatic stellate
cells) were evaluated by ELISA. Results: In Mdr2-/- mice there
enhanced biliary proliferation, IBDM and liver fibrosis compared
to WT mice. There was a significant reduction in biliary
proliferation, IBDM, liver fibrosis and mRNA expression of the
aforementioned profibrotic markers in Mdr2-/- mice that were
treated with SCT 5-27 compared to saline-treated Mdr2-/- mice.
There was a significant reduction in the levels of serum transaminases
as well as serum and cholangiocyte supernatant levels
of TGFβ1 in Mdr2-/- mice treated with SCT 5-27 compared
to controls. We also observed a significant increase in miR-
125b and let-7a in the Mdr2-/- mice treated with SCT 5-27
compared to control mice, which corresponded to decreased
mRNA expression of the biliary proliferative factors VEGF-A
and NGF. Conclusion: Inhibition of the SCT/SR axis with the
SR antagonist may represent a novel therapeutic approach
for modulating biliary proliferation and liver fibrosis during
cholestasis