Z Gastroenterol 2009; 47 - P1_30
DOI: 10.1055/s-0029-1191784

The neuronal guidance cue and survival factor, Netrin-1, in liver fibrogenesis

D Lopez 1, F Schulze 1, M Scheffler 1, S Mesghenna 2, K Wendland 1, U Töx 2, U Drebber 1, D Nierhoff 2, HP Dienes 1, M Odenthal 1
  • 1Institut für Pathologie, Universität zu Köln
  • 2Abteilung für Gastroenterologie und Hepatologie am Abdominalzentrum, Universität zu Köln

Aims: Netrin-1 has been discovered as a guidance cue for commissural axons via its receptor DCC (deleted in colorectal cancer) und the UNC5H receptor family. The netrin-1 receptors including UNC5H have been shown to be dependence receptors which induce apoptosis when devoid of their ligand. Accordingly, netrin-1 serves as a survival factor for different cell types. In the present study we investigated the expression of netrin-1 and its receptor UNC5H2 in the rat liver and its possible impact on fibrogenesis.

Methods: Hepatic stellate cells (HSC) were isolated from rats and taken in primary culture. Pattern of genes, differentially expressed during myofibroblastic transition, were evaluated by array hybridisation of total RNA isolates and validated by reverse transcription and subsequent real-time PCR. In order to study netrin-1 and UNC5H2 expression during fibrogenesis, bile-duct ligation was performed on 21 rats. Apoptosis upon fibrosis was measured by Tunnel assays. Laser-associated microdissection was used to isolate pericentral and periportal areas and compare netrin-1 and UNC5H2 expression levels in acinar zone I and III by real-time PCR.

Results: During myofibroblastic differentiation of HSC, the expression of both, netrin-1 and its receptor UNC5H2, was increased. Additionally, we demonstrate that UNC5H2 was more than 10fold enhanced upon fibrosis, whereas netrin-1 was not altered. Elevated UNC5H2 expression significantly correlates with hydroxyprolin levels (p<0.01), with inflammation (p<0.01) and apoptosis. Analyses of distribution of netrin-1 and its receptor UNC5H2 by laser microdissection of pericentral and periportal areas revealed predominant netrin-1 expression in acinar zone III.

Conclusion: The netrin-1 gradient between acinar zone III and I, in addition to highly elevated UNC5H2 expression during fibrogenesis leads to the suggestion that the netrin-1/UNC5H2 system might be involved in apoptosis shown to be a central event of fibrosis [1].

Literatur: [1] A. Canbay, S. Friedman, and G.J. Gores, Apoptosis: the nexus of liver injury and fibrosis. Hepatology 39 (2004) 273-8.

apoptosis - fibrogenesis - neuronal mediators