Plasma Endothelin Immunoreactivity in Liver Disease and the Hepatorenal Syndrome

Endothelin (ET) peptides have been implicated in the pathogenesis of several biological processes within the liver. ET levels are elevated in the circulation of patients with cirrhosis, and recent data suggest that ET may be overproduced in the liver itself in this condition. The aims of the current study were to elucidate the cellular source and expression of endothelin-1 (ET-1) in normal and injured liver, and to investigate its biological effects on stellate cells, the primary target of ETs in the liver. In normal hepatic cells, preproET-1 messenger RNA (mRNA) was detected in only nonparenchymal cells, predominantly in sinusoidal endothelial cells. After biliary fibrosis and early cirrhosis induced by bile duct ligation, preproET-1 mRNA and immunoreactive ET levels increased with progressive injury in whole liver extracts, as well as in isolated stellate and endothelial cell fractions. Eight days after bile duct ligation, the relative increase in preproET-1 mRNA was 1.6-and 7.6-fold above normal in sinusoidal endothelial and stellate cells, respectively. Additionally, immunoreactive ET peptide levels increased by 60% ؎ 27% over basal values in sinusoidal endothelial cells and 98% ؎ 40% in stellate cells. Cultured stellate cells responded dramatically to exogenous ET-1 by the spreading and up-regulation of smooth muscle ␣ actin expression. Furthermore, in early culture before cellular activation, ET-1 (10 nmol/L) caused over a twofold increase in [ 3 H]thymidine incorporation, while activated cells (i.e., those cultured for G1 week) exposed to ET-1 exhibited up to a fivefold decrease in [ 3 H]thymidine incorporation. The data indicate that not only is ET-1 overproduced by both sinusoidal endothelial and stellate cells during liver injury, but that it also has potent effects on features of stellate cell activation. We conclude that autocrine and paracrine production of ET-1 is prominent and is likely to be important in the pathogenesis of hepatic diseases. (HEPATOLOGY 1998;27:472-480.)The endothelins (ETs) form a family of 21 amino acid peptides that play an important role in many biological processes. Three unique ET species have been identified and include endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3). 1 While the major function of ETs appears to be in the local control of vascular tone, 1 these compounds have other effects, including regulation of growth and mammalian neural crest development. 2,3 ETs bind to two different G protein-coupled receptors, endothelin A (ET A ) and endothelin B (ET B ) receptors. 4 ET A receptors are found predominantly on vascular smooth muscle cells and are preferentially activated by ET-1. Rank order affinities for the ET A receptor are ET-1 Ͼ ET-2 ϾϾϾ ET-3; the affinity of ET-1 for the ET A receptor is more than 100-fold that of ET-3, while the ET B receptor has equal affinity for ET-1, ET-2, and ET-3. 4 ET receptors are present on all major rat hepatic cell types, including stellate, endothelial, and Kupffer cells, as well as hepatocytes, but saturation bi...

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“…10,[27][28][29] While these data suggest a role for ET in various parenchymal organ diseases, FIG. 5.…”

Section: Discussionmentioning

confidence: 99%

Cellular localization of endothelin-1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells

et al. 1998

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“…This is thelin). [32][33][34][35][36] To rule out an impaired kidney function caused a further argument against a stimulated NO formation in our by an activation of the renin-angiotensin-system we deterpatients with compensated liver cirrhosis. mined renin and aldosterone in our patients.…”

Section: Discussionmentioning

confidence: 99%

Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis

et al. 1997

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To investigate the role of nitric oxide (NO) with respect to In this context, some authors have postulated that patients with compensated liver cirrhosis already show hyperfiltration kidney function and liver cirrhosis, we evaluated renal function, as well as cyclic guanosine monophosphate (cGMP) and in an unstimulated state, which suggests a preponderate NOformation in the kidney. 9 However, the role of NO with NO x (nitrite/nitrate [NO 3 -/NO 2 -]) as indirect markers of NO formation in plasma and urine at rest and during amino acid respect to renal dysfunction has been ill-defined. Thus, the aim of the present study was two-fold: first, to find out if (aa)-induced glomerular hyperfiltration in patients with Child A liver cirrhosis and portal hypertension (n Å 12), and in renal function is altered in patients with compensated liver cirrhosis (Child A) with respect to glomerular filtration rate healthy controls (n Å 10). Baseline filtration rate (GFR) and effective renal plasma flow (ERPF) were significantly lower (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), and filtration fraction (FF) both before in patients with cirrhosis than in controls (GFR: mean 88 { SD 16 mL/min vs. 106 { 15 mL/min, P Å .01, ERPF: 477 { and during testing renal functional reserve (RFR Å difference between stimulated GFR and baseline GFR) by an amino 93 vs. 561{ 72 mL/min, P Å .002). In both groups amino acid (aa) infusion increased GFR, ERPF, as well as cGMP acid (aa) infusion compared with healthy controls. 5,6,[10][11][12] Second, to evaluate whether changes in renal function correand urinary NO x . Changes in GFR were similar in cirrhotic patients and controls (28.3% { 14% in cirrhotics and 26% { spond to alterations in plasma NO x (nitrite/nitrate [NO 3 -/ NO 2 -]) and cyclic guanosine monophosphate (cGMP) levels 11% in controls), but the degree of aa-induced changes in ERPF was more marked in patients with liver cirrhosis (31.8% as well as renal NO excretion as determined by urinary nitrite/nitrate and cGMP. NO x and cGMP are indirect markers { 17% vs. 18.6% { 12%, P Å .02). Plasma levels of NO x and cGMP were similar in either group at baseline and during aa of NO release, which itself, because of its short half-life, is difficult to determine in humans. infusion, whereas NO x and cGMP excretion in cirrhotics was constantly 14% to 24% lower than in the control group. We tors and vasodilators such as NO. It is also believed that NO served as controls. Throughout the study period all subjects neither is a mediator of renal hyperfiltration following aa infusion. [5][6][7][8] smoked nor took any medication. There were no vegetarians in either group and the participants continued their regular western diet that contained 0.9 { 0.15 g/kg body weight protein, as calculated from the 24-hour urine collection. 13 The 24-hour urinary soAbbreviations: NO, nitric oxide; GFR, glomerular filtration rate; ERPF, effective dium output on the day before the study was 126 { 18 mmol in renal plasma flow; RVR, renal vascu...

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“…As previously described, there are many studies showing the increased plasma ET-1 levels in patients with cirrhosis, particularly in those with ascites and hepatorenal syndrome. [9][10][11][12][13][14][15][16][17][18][19] However, the origin of ET-1 is obscure. Some workers suggest the hepatosplanchnic origin of ET-1 because high ET-1 levels were found in the hepatic vein 14,17 or portal vein.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8] Since 1992, more than 10 investigative groups have shown the increased level of plasma ET-1 in patients with cirrhosis. [9][10][11][12][13][14][15][16][17][18][19] The grade of the ET-1 elevation seems to be related to the severity of cirrhosis 13,16 and the presence or absence of ascites. 10,11,19 The highest levels were observed in hepatorenal syndrome.…”

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confidence: 99%

production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

et al. 2000

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This study was aimed to evaluate the source of endothelin-1 (ET-1) in cirrhotic patients. ET-1 is implicated in the pathogenesis of portal hypertension. However, the mechanism and source for increased plasma ET-1 in cirrhotic patients are still obscure. Plasma ET-1 levels in systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood were measured in 23 patients with cirrhosis and 8 controls with normal liver. Fourteen removed spleens were immunohistochemically studied for ET-1, CD34, CD68, and CD20. In situ hybridization was done to localize ET-1 messenger RNA (mRNA). In cirrhosis, ET-1 levels in both SMV and SPV were higher than in SV. ET-1 in SV and SPV were significantly higher in cirrhotic patients than in control patients. Three groups of cells in the spleen expressed both protein and mRNA of ET-1: endothelial cells in the sinus, which were also stained for CD34; cells in the germinal center; and cells in the marginal zone of lymphoid sheaths and follicles, which were also stained for CD20 but not for CD34 and CD68. Endothelins (ETs) are a group of three related peptides of 21 amino acids (ET-1, ET-2, and ET-3) first described as potent vasoconstrictors. 1,2 At present, it is known that ETs exert a variety of biological, physiological, and metabolic actions through two types of receptors (ET A and ET B ) in humans. [3][4][5] In recent years, much attention has been paid to the role of ET-1 in hepatic circulation, particularly in relation to portal hypertension. [6][7][8] Since 1992, more than 10 investigative groups have shown the increased level of plasma ET-1 in patients with cirrhosis. [9][10][11][12][13][14][15][16][17][18][19] The grade of the ET-1 elevation seems to be related to the severity of cirrhosis 13,16 and the presence or absence of ascites. 10,11,19 The highest levels were observed in hepatorenal syndrome. 9 However, the physiological significance of elevated ET-1 levels in cirrhosis is still controversial. The role of endotoxin or plasma volume remains to be elucidated. 10,11,15 Furthermore, the origin and elimination of plasma ET-1 in cirrhosis have not been clarified.Of late, Gerbes et al. 14 and Moller et al. 17 suggested the hepatosplanchnic origin of ET-1 because the highest ET-1 concentrations were found in hepatic venous blood. Martinet et al. 18 showed that high ET-1 levels in the portal blood were reduced after portal decompression by transjugular intrahepatic portosystemic shunt. These studies, however, did not show from which organ or organs of the splanchnic region ET-1 was released in cirrhosis and portal hypertension.The present study was prospectively aimed to clarify this problem. While measuring plasma ET-1 levels in the systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood in patients with cirrhosis of different Child-Turcotte classes and control patients with normal liver, we came to know that ET-1 was highest in the SMV in controls but that SPV ET-1 levels were significantly higher in cirrhosis.Therefore, the cellular source of ET-1 in t...

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Plasma Endothelin Immunoreactivity in Liver Disease and the Hepatorenal Syndrome

Abstract: The increase in plasma endothelin-1 and endothelin-3 concentrations in patients with the hepatorenal syndrome is consistent with the hypothesis that these substances have a role in the pathogenesis of the disease.

Cited by 352 publications

References 20 publications

Cellular localization of endothelin-1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells

Cellular localization of endothelin-1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells

Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis

production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

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