Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1.

Abstract

The endothelins (ETs) form a group of three vasoactive peptides (ET-1, ET-2, and ET-3) for which two types of cellular receptors have been identified, types A and B ET receptors (ETA and ETB receptors, respectively). To address possible targets for ETs within the liver, we isolated the four principal liver cell populations and placed them in short-term primary culture. By ligand-binding assay and mRNA levels, expression of ET receptors was greatest on hepatic lipocytes (Ito cells or fat-storing cells), which are perisinusoidal cells exhibiting features of smooth muscle cells. Moreover, lipocytes expressed both ETA and ETB receptors. The mRNA for ETB receptor, but not for ETA receptor, was detectable in sinusoidal endothelial cells and Kupffer cells; neither mRNA was detectable in hepatocytes. Both ET-1 and ET-3 elicited contraction of activated lipocytes cultured on collagen lattices; the ECSO value for ET-1 was 3 ± 1 nM and for ET-3 was 17 ± 12 nM. In cell isolates from injured liver (after administration of carbon tetrachloride), expression of ET receptors was unchanged. However, mRNA for ET-1 was significantly increased in activated lipocytes, suggesting an autocrine loop for the initiation of lipocyte contraction. The findings imply that ET-1 may play a role in regulating sinusoidal perfusion through its effect on lipocytes, particularly in iDJury states.The endothelins (ETs) are a group of three related peptides (ET-1, ET-2, and ET-3) first described as vasoconstrictors but now known to have an array of metabolic effects (1-3). Specific ET receptors also have been described and are divided into at least two types, termed type A (ETA receptor) (4, 5) and type B (ETB receptor) (6). The ETA receptor is localized largely to vascular smooth muscle and appears to mediate vasoconstrictor effects (7). The ETB receptor is present on a variety of cell types and may subserve other biologic actions of ETs (6, 7).Although studies of ETs have focused on systemic vasoregulation, these peptides may also modulate blood flow locally in specific tissues by autocrine or paracrine routes. This is of particular interest in the liver, where local changes in blood flow may be central to major pathologies such as portal hypertension, ascites formation, and hypoxic damage (8). A possible cellular target of ETs within the liver has emerged from recent work on hepatic lipocytes, which are perisinusoidal cells also known as Ito or fat-storing cells. These cells, particularly in the setting of injury and inflammation, display markers of smooth muscle cells, suggesting contractile potential (9-11).We demonstrate that ET-1 and ET-3 bind to lipocytes via high-affinity receptors and that these peptides are potent agonists of lipocyte contraction. The data have implications for the regulation of hepatic blood flow at the sinusoidal level.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate ...

Attenuation of Ischemic Liver Injury by Monoclonal Anti-Endothelin Antibody, AwETN40

“…Second, ET-I exerts its action by an autocrine or paracrine mechanism. Ito cells have a very low level of ET-I mRNA in the normal liver, but it increases significantly once the liver receives ischemic insults (27). In addition, when ET-I is produced by endothelial cells, 80% of the ET-I is released into the interstitial space rather than into the circulation (28).…”

Attenuation of Ischemic Liver Injury by Monoclonal Anti-Endothelin Antibody, AwETN40

“…Second, ET-1 exerts its action by an autocrine or paracrine mechanism. Ito cells have a very low level of ET-1 mRNA in the normal liver, but it increases significantly once the liver receives ischemic insults (27). In addition, when ET-1 is produced by endothelial cells, 80% of the ET-1 is released into the interstitial space rather than into the circulation (28).…”

Altered Endothelin-1 Signaling in Production of Thromboxane A2 in Kupffer Cells from Bile Duct Ligated Rats

“…Stimulation of Gi coupled receptors have been reported to lead to the phosphorylation of cPLA 2 and release of AA via the activation of p38 MAPK and ERK1/2, although the intermediates involved in the activation of p38 have not been fully elucidated (38)(39)(40)(41)(42)(43)(44)(45)(46)(47). KCs express ET (B) receptors coupled to Gq/G11 and Gi proteins (48)(49)(50)(51), and several reports have supported the initial findings by Qui et al of the requirements of both a transient increase in calcium and phosphorylation of ser505, via p38 MAPK or ERK1/2, for the full activation of cPLA 2 and AA release in macrophages (28,34,35).…”