Bennett Robert G, Dalton Shana R, Mahan Katrina J, Gentry-Nielsen Martha J, Hamel Frederick G, Tuma Dean J
Department of Medical Research, Veterans Affairs Medical Center, 4001 Woolworth Avenue, Omaha, NE 68105, USA.
Biochem Pharmacol. 2007 Apr 1;73(7):1033-40. doi: 10.1016/j.bcp.2006.12.007. Epub 2006 Dec 10.
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.
多肽激素松弛素对包括肝脏在内的多种组织具有抗纤维化作用。肝星状细胞（HSC）从静止状态转分化为分泌纤维状胶原蛋白的活化肌成纤维细胞表型是肝纤维化进展的核心。松弛素可抑制HSC活化标志物，但肝脏中松弛素受体的表达尚不清楚。本研究的目的是确定活化HSC中松弛素受体LGR7和LGR8的表达。用松弛素或分别为LGR8和LGR7的选择性激活剂的松弛素相关肽InsL3或松弛素-3处理HSC可诱导cAMP的产生。静止的HSC表达低水平的LGR7，但不表达LGR8。在向活化表型进展过程中，两种受体的表达均显著增加。免疫细胞化学证实活化的HSC中存在两种受体。在正常大鼠肝脏中，LGR7表达水平低，而LGR8不表达。在肝硬化肝脏中，两种受体的表达均显著增加。免疫组织化学在正常肝脏中未检测到这两种受体，但在肝硬化中LGR7和LGR8均易于检测到。这些结果在人肝硬化组织中得到证实，另外还发现在非肝硬化组织中偶尔有窦周LGR7免疫反应性。总之，在培养中随着HSC的活化，LGR7和LGR8的表达增加。肝硬化也导致这两种受体的表达增加。因此，刺激LGR8和LGR7的药物可能在治疗上有助于限制肝损伤中肝星状细胞的活化。
