Cross talk between toll‐like receptor‐4 signaling and angiotensin‐II in liver fibrosis development in the rat model of non‐alcoholic steatohepatitis

Shirai, Yusaku; Yoshiji, Hitoshi; Noguchi, Ryuichi; Kaji, Kosuke; Aihara, Yosuke; Douhara, Akitoshi; Moriya, Kyoji; Namisaki, Tadashi; Kawaratani, Hideto; Fukui, Hiroshi

doi:10.1111/jgh.12112

Cited by 47 publications

(42 citation statements)

References 42 publications

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“…However, AT-II could not stimulate the signaling pathways downstream of TLR4 without LPS because TLR4 is not the downstream receptor of AT-II. LPS with AT-II significantly promoted LPS-induced activation and ARB significantly blocked AT-II mediated TLR4-LPS signaling cascade, leading to significant reduction in TGF-b1 production in Ac-HSC [14]. These findings reinforce the notion that cross talk between AT-II and TLR4 signaling plays a substantial role in the liver fibrosis development by regulating TGF-b1 production in Ac-HSCs.…”

Section: Discussionsupporting

confidence: 79%

“…The inhibitory effects of ARB mostly coincided with the suppression of activated hepatic stellate cells (Ac-HSC) [13]. Moreover, we demonstrated AT-II augmented LPS-TLR4 signaling through AT1R and ARB improved hepatic fibrogenesis and reduced TLR4-mediated innate immune signaling in Ac-HSC [14]. These results indicate that combined UDCA and ARB may have utility in the treatment of NASH.…”

Section: Introductionmentioning

confidence: 65%

“…In vitro study confirmed the suppressive effect of ARB was because of direct inhibition of Ac-HSC activation. Furthermore, we recently demonstrated that AT-II is critically involved in the up-regulation of TLR4 expression through stimulation of AT1R in Ac-HSC [14]. AT-II augmented the LPS-TLR4 signaling cascade via up-regulation of TLR4.…”

Section: Discussionmentioning

confidence: 97%

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Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis

et al. 2015

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 65%

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Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis

et al. 2015

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“…Second, Ekihiro S, et al isolated primary quiescent HSCs followed by magnetic antibody cell sorting with antibody against F4/80 antigen and CD11b-conjugated microbeads to remove Kupffer cells and macrophages. This procedure may activate primary quiescent HSCs and up-regulate TLR4 expression, because primary quiescent HSCs are easily to be activated even by culturing for certain time in dish [36]. Therefore, an efficient crosstalk must need up-regulation of TLR4.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Shirai et al [36] reported that Ang II could up-regulate TLR4 mRNA expression in activated rat HSCs by culturing on plastic plates for 7 days. This is consistent with our observations both on rat HSC cell line and primary HSCs, in which TLR4 protein levels were assessed by western blotting in vitro and immunofluorescence in vivo .…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Facilitates Fibrogenic Effect of TGF-β1 through Enhancing the Down-Regulation of BAMBI Caused by LPS: A New Pro-Fibrotic Mechanism of Angiotensin II

Meng

et al. 2013

PLoS ONE

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Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isn't fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-β1) through up-regulation of toll-like receptor 4 (TLR4) and enhancing down-regulation of TGF-β1 inhibitory pseudo-receptor—BAMBI caused by LPS in hepatic stellate cells (HSCs). Firstly, the synergistic effects of angiotensin II, TGF-β1 and LPS on collagen 1α production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-β1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-β1 were used. We also found that only LPS and TGF-β1 weren't enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1) blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS-TLR4 pathway signaling and further down-regulates expression of BAMBI through up-regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF-β1. Angiotensin II, LPS and TGF-β1 act synergistically during hepatic fibrogenesis, showing crosstalks between angiotensin II-AT1, LPS-TLR4 and TGF-β1-BAMBI signal pathways in rat HSCs.

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Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on hepatic fibrosis

Namisaki

Moriya

Kitade

et al. 2017

Hepatology Communications

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The farnesoid X receptor (FXR) agonist, a bile acid‐activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1 mL/kg pig serum (PS) twice a week, whereas Fischer‐344 rats were fed a choline‐deficient, L‐amino acid‐defined diet (CDAA). The in vitro and in vivo effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS‐administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor β1 and toll‐like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens‐1 disruption, whereas losartan directly suppressed activated‐HSC (Ac‐HSC) regulation. The in vitro inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor β1, toll‐like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor‐κB and mothers against decapentaplegic homolog 3 in Ac‐HSC were almost in parallel. Losartan directly inhibited the regulation of Ac‐HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS‐administered OLETF and CDAA‐treated rats. Conclusion: INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac‐HSC proliferation. Combined therapy may represent a promising novel approach for NASH. (Hepatology Communications 2017;1:928–945)

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Cross talk between toll‐like receptor‐4 signaling and angiotensin‐II in liver fibrosis development in the rat model of non‐alcoholic steatohepatitis

Abstract: These studies indicated that the cross talk between TLR4 signaling cascade and AT-II plays a pivotal role in liver fibrosis development in non-alcoholic steatohepatitis.

Cited by 47 publications

References 42 publications

Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis

Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis

Angiotensin II Facilitates Fibrogenic Effect of TGF-β1 through Enhancing the Down-Regulation of BAMBI Caused by LPS: A New Pro-Fibrotic Mechanism of Angiotensin II

Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on hepatic fibrosis

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