Relaxin receptors in hepatic stellate cells and cirrhotic liver

Robert G Bennett, Shana R. Dalton, Katrina J. Mahan, Martha J. Gentry-Nielsen, Frederick G Hamel, Dean J. Tuma

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The polypeptide hormone relaxin has antifibrotic effects on a number of tissues, including the liver. Central to the progression of hepatic fibrosis is the transdifferentiation of hepatic stellate cells (HSC) from a quiescent state to an activated, myofibroblastic phenotype that secretes fibrillar collagen. Relaxin inhibits markers of HSC activation, but relaxin receptor expression in the liver is unclear. The purpose of this study was to determine the expression of the relaxin receptors LGR7 and LGR8 in activated HSC. Production of cAMP was induced by treatment of HSC with relaxin, or the relaxin-related peptides InsL3 or relaxin-3, selective activators of LGR8 and LGR7, respectively. Quiescent HSC expressed low levels of LGR7 but not LGR8. During progression to the activated phenotype, expression of both receptors increased markedly. Immunocytochemistry confirmed the presence of both receptors in activated HSC. In normal rat liver, LGR7, but not LGR8, was expressed at low levels. In cirrhotic liver, expression of both receptors significantly increased. Neither receptor was detectable in normal liver by immunohistochemistry, but both LGR7 and LGR8 were readily detectable in cirrhosis. These results were confirmed in human cirrhotic tissue, with the additional finding of occasional perisinusoidal LGR7 immunoreactivity in non-cirrhotic tissue. In conclusion, the expression of LGR7 and LGR8 is increased with activation of HSC in culture. Cirrhosis also caused increased expression of both receptors. Therefore, agents that stimulate LGR8 and LGR7 may be therapeutically useful to limit the activation of hepatic stellate cells in liver injury.

Original languageEnglish (US)
Pages (from-to)1033-1040
Number of pages8
JournalBiochemical Pharmacology
Volume73
Issue number7
DOIs
StatePublished - Apr 1 2007

Fingerprint

Hepatic Stellate Cells
Liver
Relaxin
Fibrosis
Chemical activation
Tissue
Immunohistochemistry
Fibrillar Collagens
Phenotype
relaxin receptors
Peptide Hormones
Rats
Cell Culture Techniques
Peptides
Wounds and Injuries

Keywords

  • Fibrosis
  • InsL3
  • LGR7
  • LGR8
  • Relaxin-3

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Relaxin receptors in hepatic stellate cells and cirrhotic liver. / Bennett, Robert G; Dalton, Shana R.; Mahan, Katrina J.; Gentry-Nielsen, Martha J.; Hamel, Frederick G; Tuma, Dean J.

In: Biochemical Pharmacology, Vol. 73, No. 7, 01.04.2007, p. 1033-1040.

Research output: Contribution to journalArticle

Bennett, Robert G ; Dalton, Shana R. ; Mahan, Katrina J. ; Gentry-Nielsen, Martha J. ; Hamel, Frederick G ; Tuma, Dean J. / Relaxin receptors in hepatic stellate cells and cirrhotic liver. In: Biochemical Pharmacology. 2007 ; Vol. 73, No. 7. pp. 1033-1040.
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AB - The polypeptide hormone relaxin has antifibrotic effects on a number of tissues, including the liver. Central to the progression of hepatic fibrosis is the transdifferentiation of hepatic stellate cells (HSC) from a quiescent state to an activated, myofibroblastic phenotype that secretes fibrillar collagen. Relaxin inhibits markers of HSC activation, but relaxin receptor expression in the liver is unclear. The purpose of this study was to determine the expression of the relaxin receptors LGR7 and LGR8 in activated HSC. Production of cAMP was induced by treatment of HSC with relaxin, or the relaxin-related peptides InsL3 or relaxin-3, selective activators of LGR8 and LGR7, respectively. Quiescent HSC expressed low levels of LGR7 but not LGR8. During progression to the activated phenotype, expression of both receptors increased markedly. Immunocytochemistry confirmed the presence of both receptors in activated HSC. In normal rat liver, LGR7, but not LGR8, was expressed at low levels. In cirrhotic liver, expression of both receptors significantly increased. Neither receptor was detectable in normal liver by immunohistochemistry, but both LGR7 and LGR8 were readily detectable in cirrhosis. These results were confirmed in human cirrhotic tissue, with the additional finding of occasional perisinusoidal LGR7 immunoreactivity in non-cirrhotic tissue. In conclusion, the expression of LGR7 and LGR8 is increased with activation of HSC in culture. Cirrhosis also caused increased expression of both receptors. Therefore, agents that stimulate LGR8 and LGR7 may be therapeutically useful to limit the activation of hepatic stellate cells in liver injury.

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