Expression and function of S-endoglin, a rat specific splice variant of endoglin, in liver cells

Background: Liver fibrosis, characterized by excess deposition of extracellular matrix (ECM), is based on the activation hepatic stellate cells (HSC). Activation and ECM production of HSC is regulated by TGF-β1. Full length endoglin (L-endoglin), an accessory TGF-β1 has been shown to modulate these responses [1–3]. Nevertheless, in human and mouse a splice variant of endoglin, i.e. S-endoglin has been described, with significant altered functions compared to L-endoglin [4–6]. A similar splice variant of endoglin in rat has not been identified so far. Methods and Results: We show here that all cells of the liver, which have been shown to express the mRNA of L-endoglin are also positive for the mRNA of S-endoglin (RT-PCR and Northern blot). In contrast to the truncated S-endoglins in human and mouse, the retention of an intron without a stop-codon in rat, results in a longer protein. Heterologous co-expression of rat S-endoglin with TßRII in COS-7 confirms an interaction of both receptors (co-IP) and a phosphorylation of S-endoglin by TßRII. Similar results are achieved by overexpression of S-endoglin in the HSC cell line CFSC-2G. In addition, S-endoglin in a short term time course strongly enhances TGF-β1-mediated Smad1/Smad5 activation. TGF-β1-regulated long term responses, e.g. alpha-SMA, Collagen type I and CTGF, are also influenced by S-endoglin. Conclusions: L-endoglin positive liver cells express in addition a longer splice variant of endoglin, i.e. S-endoglin. This yet unidentified splice variant is involved in TGF-β1-signaling and modulates short term (Smad-activation) and long term (alpha-SMA and Collagen type I expression) responses of TGF-β1.