Acute cholestasis-induced renal failure: Effects of antioxidants and ligands for the thromboxane A2 receptor

Holt, Stephen G; Marley, Richard; Fernando, Bimbi; Harry, David; Anand, Radhi; Goodier, David; Moore, Kevin

doi:10.1046/j.1523-1755.1999.00252.x

Cited by 81 publications

(49 citation statements)

References 25 publications

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“…Isoprostanes and liver fibrosis M Comporti et al appears to act through the activation of receptors analogous to those for TXA 2 r, 17 an effect believed to be important in explaining the Hepato-Renal Syndrome. 34 Other biological effects of 8-epi-PGF 2a are those on muscle vascular cells and on endothelial cells in which DNA synthesis and cell proliferation is stimulated. 33,35 These effects also are probably due to activation of receptors related to TXA 2 r. Finally, 8-epi-PGF 2a seems to mediate the increased production of TGF-b1 in kidney mesangial and glomerular cells exposed to high ambient glucose such as that produced by streptozotocin-induced diabetes.…”

Section: Discussionmentioning

confidence: 99%

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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Carbon tetrachloride (CCl 4 )-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F 2 -isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F 2 -isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl 4 -induced hepatic fibrosis, plasma F 2 -isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F 2 -isoprostanes in the concentration range found in the in vivo studies (10 À9 -10 À8 M), a striking increase in DNA synthesis (reversed by the thromboxane A 2 antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F 2 -isoprostanes markedly increased the production of transforming growth factor-b1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F 2 -isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.

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Section: Discussionmentioning

confidence: 99%

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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“…Besides being the markers of oxidative stress, F 2 -isoprostanes appear to be mediators of important biological effects, such as the vasoconstriction of renal glomerular arterioles (possible explanation of the Hepato-Renal Syndrome) 7 or the effects on vascular muscle cells and on endothelial cells, 8,9 in which cellular proliferation is stimulated. The effects of F 2 -isoprostanes are also observed on kidney mesangial and glomerular cells exposed to high glucose concentration, in which increased production of transforming growth factor-b (TGF-b) is seen, 10 and similar effects are reported on retinal vessels.…”

mentioning

confidence: 99%

F2-isoprostane receptors on hepatic stellate cells

Gardi

Arezzini

Monaco

et al. 2008

Laboratory Investigation

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F 2 -isoprostanes are considered as the most reliable markers of oxidative stress and can be used to evaluate the oxidative status in a number of human pathologies. Besides being markers of oxidative stress, F 2 -isoprostanes proved to be mediators of important biological effects and would act through the activation of receptors analogous to those for thromboxane A 2 . In a previous work, we provided evidence that F 2 -isoprostanes, generated during carbon tetrachlorideinduced hepatic fibrosis, mediate hepatic stellate cell (HSC) proliferation and collagen hyperproduction. To investigate whether TxA 2 receptor (TxA 2 r or TPr) is involved in the effects of F 2 -isoprostanes on HSC, experiments on DNA synthesis were carried out in the presence of 8-epi-prostaglandin F 2a (8-epi-PGF 2a ) or the TxA 2 r-specific agonist I-Both agonists significantly stimulated DNA synthesis, which was almost completely inhibited by the TxA 2 r-specific, suggesting that much of the effect of 8-epi-PGF 2a is mediated by the TxA 2 r. Further studies showed that increasing concentrations of SQ29548 progressively inhibit DNA synthesis, suggesting a possible competitive antagonism between the two molecules. In addition, we demonstrated that the stimulatory effect of 8-epi-PGF 2a on collagen synthesis could be mediated by TxA 2 r. The occurrence of TxA 2 r on HSC was also investigated using western blotting analysis and immunocytochemistry, which reveals that TP is distributed both on plasma membranes and within the cells. Moreover, binding studies indicated the presence of a specific binding site for 3 H-SQ29548 on HSC. Competition binding studies indicated that 8-epi-PGF 2a and I-BOP were both able to displace 3 H-SQ29548 binding with a very different affinity (K i ¼ 4.14±1.9 Â 10 À6 M and K i ¼ 1.15±0.3 Â 10 À9 M, respectively), suggesting the involvement of a modified form of isoprostane receptor, homologous to the classic thromboxane A 2 -binding site in F 2 -isoprostanes-evoked responses on HSC.

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“…Moreover, the severity of hyperbilirubinemia correlates with high lipid peroxide levels and low anti-oxidant levels (10). Exaggerated lipid peroxidation, oxidative stress and accumulation of toxic hydrophobic bile salts within hepatocytes in jaundiced rats cause hepatocyte toxicity, which leads to liver damage.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the severity of jaundice correlates with high lipid peroxide levels and low anti-oxidant levels (10). The expression of iNOS can be regulated at the level of transcription, and nuclear factor kappa B (NF-κB) activation is essential for its expression (11).…”

Section: Introductionmentioning

confidence: 99%

The monitoring of progress in apoptosis of liver cells in bile duct-ligated rats

Dirlik

Canbaz²,

Apa³

et al. 2009

Turk J Gastroenterol

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Acute cholestasis-induced renal failure: Effects of antioxidants and ligands for the thromboxane A2 receptor

Abstract: NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.

Cited by 81 publications

References 25 publications

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

F2-isoprostane receptors on hepatic stellate cells

The monitoring of progress in apoptosis of liver cells in bile duct-ligated rats

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