Increased renal and vascular cytosolic phospholipase A<sub>2</sub>activity in rats with cirrhosis and ascites

Niederberger, M; Ginès, Pere; Martin, Pierre‐Yves; John, Judy St.; Woytaszek, Paul; Xu, Lieming; Tsai, Pei‐San; Nemenoff, Raphael A.; Schrier, Robert W.

doi:10.1002/hep.510270108

Cited by 17 publications

(7 citation statements)

References 40 publications

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“…In addition, it had been reported that the activation of cPLA 2 was highly dependent on a rise in intracellular calcium concentration, which leads to the translocation of the enzyme from the cytosol to nucleus, allowing it access to its substrate [39]. Consistent with previous findings [52,53], in the present study, the protein levels of cPLA 2 and sPLA 2 were significantly increased in cirrhotic livers compared with normal livers. However, chronic blocking of CB 1 receptors only significantly inhibited the up-regulated hepatic cPLA 2 protein, rather than hepatic sPLA 2 protein, in cirrhotic livers ( Figure 3).…”

Section: Discussionsupporting

confidence: 91%

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Yang

Lin

Huang³

et al. 2007

Clinical Science

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Recent studies have shown that the activated endocannabinoid system participates in the increase in IHR (intrahepatic resistance) in cirrhosis. The increased hepatic production of vasoconstrictive eicosanoids is involved in the effect of endocannabinoids on the hepatic microcirculation in cirrhosis; however, the mechanisms of these effects are still unknown. The aim of the present study was to investigate the effects of chronic CB(1) (cannabinoid 1) receptor blockade in the hepatic microcirculation of CBL (common bile-duct-ligated) cirrhotic rats. After 1 week of treatment with AM251, a specific CB(1) receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB(2) (thromboxane B(2)), 6-keto PGF(1alpha) (prostaglandin F(1alpha)) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB(1) receptor, TGF-beta(1) (transforming growth factor beta(1)), cPLA(2) [cytosolic PLA(2) (phospholipase A(2))], sPLA(2) (secreted PLA(2)) and collagen deposition were also measured. In AM251-treated cirrhotic rats, a decrease in portal venous pressure was associated with the decrease in IHR and SMA blood flow. Additionally, the protein levels of hepatic CB(1) receptor, TGF-beta(1), cPLA(2) and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB(2) and Cys-LTs in perfusates, were significantly decreased after 1 week of AM251 treatment in cirrhotic rats. Furthermore, acute infusion of AM251 resulted in a decrease in SMA blood flow and an increase in SMA resistance in CBL rats. In conclusion, the chronic effects of AM251 treatment on the intrahepatic microcirculation were, at least partly, mediated by the inhibition of hepatic TGF-beta(1) activity, which was associated with decreased hepatic collagen deposition and the activated PLA(2)/eicosanoid cascade in cirrhotic livers.

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Section: Discussionsupporting

confidence: 91%

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Yang

Lin

Huang³

et al. 2007

Clinical Science

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“…This is confirmed by data obtained in the present study, where we observed a significantly higher urinary excretion of TXB 2 and 6-keto-PGF 1α , indexes of renal TXA 2 or PGI 2 generation respectively, as well as of PGF 2α and PGE 2 in cirrhotic patients than in healthy subjects. The increased urinary excretion of AA metabolites indicates an activation of the renal PG system, an event related to the induction of phospholipase A 2 (PLA 2 ) activity within the kidney [31,32]. The urinary excretion rate of 11-dehydro-TXB 2 was also significantly higher in cirrhotic patients than in control subjects, confirming previous data from our group [33] and other investigators [34].…”

Section: Table 2 Plasma Lipids (A) and Phospholipids (B) And Rbc (C) supporting

confidence: 87%

Effects of dietary supplementation with arachidonic acid on platelet and renal function in patients with cirrhosis

et al. 2004

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Advanced cirrhosis is associated with reduced platelet function and altered renal function and sodium handling. Arachidonic acid (AA) metabolites contribute to platelet aggregation and to maintain the response to diuretics in advanced cirrhosis. In the present study, we tested the effects of a dietary supplementation for 8 weeks with a triacylglycerol (triglyceride) enriched in AA (ARASCO; 4 g/day) or oleic acid (OA) on plasma and membrane fatty acid composition, platelet aggregation and renal prostaglandin (PG) metabolism. At baseline, all patients had reduced platelet aggregation. Patients treated with AA showed a significant increase in the percentage of AA in plasma lipids and membrane phospholipids. These changes were associated with an increased platelet aggregation in response to collagen (from 55.83 +/- 20.63 to 67.67 +/- 14.44%; P<0.05). At baseline, all urinary AA metabolites, including PGE2, 6-keto-PGF1alpha, 8-epi-PGF2alpha and 11-dehydro-thromboxane B2, were elevated in cirrhotic patients when compared with a group of normal subjects. After furosemide treatment, urinary excretion of 11-dehydro-thromboxane B2 increased significantly. Supplementation with AA did not result in any significant change in urinary PG excretion either before or after diuretic administration. The results of the present study show that dietary supplementation with AA effectively increases the levels of this fatty acid in plasma and membrane phospholipids and improves platelet aggregation. These data suggest a possible novel approach to the treatment of the haemostatic defect observed in these patients.

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“…While one previous study reported that renal cPLA 2 activity was increased during cirrhosis (18), ours is the first report to conclusively link the entire arachidonic acid/cPLA 2 and EET/ CYP-450 pathway to the exaggerated ACh-induced renal vasodilation during cirrhosis. We showed that both cPLA 2 expression and activity are upregulated in the kidneys of CBDL rats.…”

Section: Discussionmentioning

confidence: 47%

“…cPLA 2 activity was measured as described previously (18). Briefly, a small amount of frozen kidney cortex was homogenized in 1 to 2 ml of assay buffer containing 50 mM HEPES, pH 7.4, 250 mM sucrose, 1 mM EDTA, 1 mM EGTA, 20 M leupeptin, 20 M pepstatin, 0.1 mM phenylmethsulfonyl fluoride, and 1000 U/ml aprotinin.…”

Section: Assay Of Cpla2 Activitymentioning

confidence: 99%

Increased Epoxyeicosatrienoic Acid Formation in the Rat Kidney during Liver Cirrhosis

Miyazono

Zhu

Nemenoff³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Vascular complications during liver cirrhosis are often severe, particularly in the kidney. These complications are the result of complex and poorly understood interactions between the injured liver and other organs such as the lungs, heart, and kidney. The purpose of this study was to investigate the alterations to renal hemodynamics during cirrhosis, focusing on the actions of epoxyeicosatrienoic acids (EET), known to be potent regulators of renal hemodynamics. Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 wk after either the sham or CBDL surgery. Vasoreactivity was assessed in isolated perfused kidneys. cPLA 2 expression and cytochrome P450 (CYP450) expression were measured using Western blot. cPLA 2 enzymatic activity was measured by radioenzymatic assay. EET production was measured using rpHPLC analysis. The major findings were that kidneys from CBDL rats had significantly greater acetylcholine-induced vasodilation that was partially blocked by nitric oxide (NO) and prostaglandin inhibition and fully blocked by the combined inhibition of NO, prostaglandins, and CYP450 metabolites. Expression and activity of cPLA 2 in CBDL kidneys was increased, providing arachidonic acid substrate to the CYP450 enzymes. Finally, expression and activity of CYP450 enzymes was elevated in CBDL kidneys, resulting in significantly greater production of the vasodilating 11,12-EET and 14,15-EET. While it is well documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, our data clearly demonstrate that endogenous production of EET is increased in cirrhotic kidneys. This may be a homeostatic response to preserve renal perfusion.Endothelium-dependent vasodilation is an important regulatory mechanism in the kidney. Many studies indicate that peripheral vasodilation of splanchnic organs may be the leading factor causing the renal dysfunction of cirrhosis (for review, see reference 1). Endothelial cells produce a wide array of biologic active agents that regulate vascular tone. These agents include NO, prostaglandin, and an unidentified substance that hyperpolarizes vascular smooth muscle called endothelium-derived hyperpolarizing factor (EDHF). The biologic actions of epoxyeicosatrienoic acids (EET) make them a strong candidate for being EDHF, because EET dilate blood vessels by activating vascular smooth muscle calcium-activated K ϩ (K Ca ) channels resulting in membrane hyperpolarization. EET are produced from arachidonic acid cleaved from membrane-associated phospholipid pools by phospholipase-A2 (cPLA 2 ) (2-4) and are further metabolized by specific cytochrome P450 (CYP450) enzymes (5-9). It is known that CYP450 2C isoforms are responsible for the majority of EET biosynthesis in the rat kidney, and CYP 2C11, 2C23, and 2C24 are the predominant 2C isoforms expressed in the male rat kidney (10 -12). However, the vascular sites of action responsible for the CYP component in cirrhotic rat kidney a...

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Increased renal and vascular cytosolic phospholipase A₂activity in rats with cirrhosis and ascites

Cited by 17 publications

References 40 publications

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Effects of dietary supplementation with arachidonic acid on platelet and renal function in patients with cirrhosis

Increased Epoxyeicosatrienoic Acid Formation in the Rat Kidney during Liver Cirrhosis

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Increased renal and vascular cytosolic phospholipase A2activity in rats with cirrhosis and ascites

Cited by 17 publications

References 40 publications

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Effects of dietary supplementation with arachidonic acid on platelet and renal function in patients with cirrhosis

Increased Epoxyeicosatrienoic Acid Formation in the Rat Kidney during Liver Cirrhosis

Contact Info

Product

Resources

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Increased renal and vascular cytosolic phospholipase A₂activity in rats with cirrhosis and ascites