Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice. Academic Article uri icon


  • In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as -calcitonin gene-related peptide (-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 1 and -smooth muscle (-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 1 and -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.

published proceedings

  • Am J Physiol Gastrointest Liver Physiol

author list (cited authors)

  • Glaser, S., Gaudio, E., Renzi, A., Mancinelli, R., Ueno, Y., Venter, J., ... Alpini, G.

citation count

  • 30

complete list of authors

  • Glaser, Shannon||Gaudio, Eugenio||Renzi, Anastasia||Mancinelli, Romina||Ueno, Yoshiyuki||Venter, Julie||White, Mellanie||Kopriva, Shelley||Chiasson, Valorie||DeMorrow, Sharon||Francis, Heather||Meng, Fanyin||Marzioni, Marco||Franchitto, Antonio||Alvaro, Domenico||Supowit, Scott||DiPette, Donald J||Onori, Paolo||Alpini, Gianfranco

publication date

  • August 2011