title: Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice.
abstract: In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as α-calcitonin gene-related peptide (α-CGRP). There is no evidence that the sensory neuropeptide substance P (SP) regulates cholangiocyte hyperplasia. Wild-type (WT, (+/+)) and NK-1 receptor (NK-1R) knockout (NK-1R(-/-)) mice underwent sham or BDL for 1 wk. Then we evaluated 1) NK-1R expression, transaminases, and bilirubin serum levels; 2) necrosis, hepatocyte apoptosis and steatosis, and the number of cholangiocytes positive by CK-19 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling in liver sections; 3) mRNA expression for collagen 1α and α-smooth muscle (α-SMA) actin in total liver samples; and 4) PCNA expression and PKA phosphorylation in cholangiocytes. In cholangiocyte lines, we determined the effects of SP on cAMP and D-myo-inositol 1,4,5-trisphosphate levels, proliferation, and PKA phosphorylation. Cholangiocytes express NK-1R with expression being upregulated following BDL. In normal NK-1R(-/-) mice, there was higher hepatocyte apoptosis and scattered hepatocyte steatosis compared with controls. In NK-1R (-)/(-) BDL mice, there was a decrease in serum transaminases and bilirubin levels and the number of CK-19-positive cholangiocytes and enhanced biliary apoptosis compared with controls. In total liver samples, the expression of collagen 1α and α-SMA increased in BDL compared with normal mice and decreased in BDL NK-1R(-/-) compared with BDL mice. In cholangiocytes from BDL NK-1R (-)/(-) mice there was decreased PCNA expression and PKA phosphorylation. In vitro, SP increased cAMP levels, proliferation, and PKA phosphorylation of cholangiocytes. Targeting of NK-1R may be important in the inhibition of biliary hyperplasia in cholangiopathies.
authors: Division of Research, Central Texas Veterans Health Care System, Scott & White and Texas A&M Health Science Center College of Medicine, Temple, USA.
authors: Shannon
authors: S
authors: Glaser
authors: Eugenio
authors: E
authors: Gaudio
authors: Anastasia
authors: A
authors: Renzi
authors: Romina
authors: R
authors: Mancinelli
authors: Yoshiyuki
authors: Y
authors: Ueno
authors: Julie
authors: J
authors: Venter
authors: Mellanie
authors: M
authors: White
authors: Shelley
authors: S
authors: Kopriva
authors: Valorie
authors: V
authors: Chiasson
authors: Sharon
authors: S
authors: DeMorrow
authors: Heather
authors: H
authors: Francis
authors: Fanyin
authors: F
authors: Meng
authors: Marco
authors: M
authors: Marzioni
authors: Antonio
authors: A
authors: Franchitto
authors: Domenico
authors: D
authors: Alvaro
authors: Scott
authors: S
authors: Supowit
authors: Donald J
authors: DJ
authors: DiPette
authors: Paolo
authors: P
authors: Onori
authors: Gianfranco
authors: G
authors: Alpini
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