Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats

Bataller, Ramón; Gäbele, Erwin; Parsons, Christopher J.; Morris, Terry; Yang, Liu; Schoonhoven, Robert; Brenner, David A.; Rippe, Richard A.

doi:10.1002/hep.20665

Cited by 153 publications

(164 citation statements)

References 44 publications

(35 reference statements)

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“…AT-II increased TGF-ß gene expression in a dose-dependent manner in activated HSCs in vitro (20). We and others reported that suppression of AT-II by ACE-I markedly attenuated experimental liver fibrosis development and suppressed TGF-ß (3,20).…”

Section: Introductionmentioning

confidence: 79%

“…The increased number of HSCs during liver fibrogenesis reflects the activity of several growth factors (1). Among the growth factors, transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF) are key mediators in liver fibrogenesis (3,4). Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM), which leads to a severe pathological disturbance in the liver.…”

Section: Introductionmentioning

confidence: 99%

“…It had been believed that hepatic fibrosis was a passive and irreversible process due to the collapse of the hepatic parenchyma and its substitution with collagen-rich tissue. However, improved understanding of the mechanism underlying hepatic fibrosis revealed that even advanced liver fibrosis is potentially reversible (3,4). It has been reported that the risk of hepatocellular carcinoma (HCC) increases with the progression of hepatic fibrosis (14).…”

Section: Introductionmentioning

confidence: 99%

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Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Yoshiji¹,

Kuriyama²,

Noguchi³

et al. 2006

Int J Mol Med

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Abstract. Both platelet-derived growth factor (PDGF) and transforming growth factor-ß (TGF-ß) are known to be pivotal cytokines in liver fibrosis development. The aim of our current study was to elucidate the effects of dual inhibition of PDGF and TGF-ß by combination of the clinically used imatinib mesylate (STI-571) and perindopril (an ACEinhibitor; ACE-I), respectively, on ongoing liver fibrosis development in rats. The effects of STI-571 and ACE-I at clinically comparable low doses were examined in a rat model of CCl4-induced liver fibrogenesis. Treatment with both STI-571 and ACE-I inhibited liver fibrogenesis and suppressed activation of hepatic stellate cells (HSCs). Administration of both agents exerted a more potent inhibitory effect than administration of either single agent. Our in vitro study demonstrated that STI-571 and ACE-I suppressed PDGF receptor (PDGFR) phosphorylation and TGF-ß expression in activated HSCs, respectively. Dual suppression of PDGF and TGF-ß with a combination of clinically comparable low doses of STI-571 and ACE-I exerted a significant inhibitory effect on ongoing liver fibrosis development. Since both agents are widely used in clinical practice, this combination therapy may provide a new strategy against liver fibrosis in the future.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Yoshiji¹,

Kuriyama²,

Noguchi³

et al. 2006

Int J Mol Med

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show abstract

“…An increase in hepatic transforming growth factor β1 (TGF-β1) and pro-inflammatory cytokine levels was attenuated in AT1-R knockout mice compared to WT mice [11] . Furthermore, Bataller et al [12] demonstrated that increased systemic Angiotensin (Ang) II augments hepatic fibrosis and promotes inflammation, oxidative stress, and thrombogenic events. Telmisartan shows the greatest affinity for the AT1-R and exhibits the longest half-life of the ARBs that are currently available [13] .…”

Section: Introductionmentioning

confidence: 99%

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Liu

Wen

et al. 2012

Acta Pharmacol Sin

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Aim: To evaluate the antifibrotic effect of telmisartan, an angiotensin II receptor blocker, in bile duct-ligated rats. Methods: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats, model rats underwent common bile duct ligation (BDL), and BDL rats treated with telmisartan (8 mg/kg, po, for 4 weeks). The animals were sacrificed on d 29, and liver histology was examined, the Knodell and Ishak scores were assigned, and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining. The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot, respectively. Results: The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35, P=0.015). However, there was no significant difference in inflammation between the two groups, both of which showed moderate inflammation. Histologically, treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis. Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS, and decreased the mRNA levels of ACE, angiotensin II type 1 receptor (AT1-R), collagen type III, and transforming growth factor β1 (TGF-β1). Moreover, treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins, and inhibited the expression levels of ACE and AT1-R protein. Conclusion:Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.

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“…The effects of Ang II on hepatic stellate cells (HSC) has been extensively studied (Bataller et al 2005(Bataller et al , 2003a(Bataller et al , b, 2000Wei et al 2001;Yokohama et al 2006;Zhang et al 2003), yet little information exists on the effect of Ang-(1-7) on these cells. Most studies using cell culture use culture medium supplemented with fetal calf serum (FCS) to encourage cell growth.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research

et al. 2008

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Cell culture experiments often employ the use of culture media that contain fetal calf serum (FCS). The angiotensin peptides angiotensin II and angiotensin 1-7 have opposing effects with angiotensin converting enzyme 2 (ACE2) being the enzyme predominantly responsible for generating angiotensin 1-7 from angiotensin II. The effect of FCS on angiotensin peptides has not previously been described. We have shown that FCS has ACE2 enzyme activity capable of degrading angiotensin II and generating angiotensin 1-7. Researchers should be aware that FCS possesses ACE2 activity and that heat-treating FCS to 56°C only partially inhibits this enzyme activity, whereas heat-treating to 70°C completely abolishes ACE2 activity.

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Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats

Cited by 153 publications

References 44 publications

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research

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