Rapamycin Ameliorates Inflammation and Fibrosis in the Early Phase of Cirrhotic Portal Hypertension in Rats through Inhibition of mTORC1 but Not mTORC2

A previous study has demonstrated that Ganshuang granule (GSG) plays an anti‐fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)‐autophagy plays an important role. We attempted to investigate the role of mTOR‐autophagy in anti‐fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti‐fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti‐fibrotic effect. 3‐methyladenine (3‐MA) and Insulin‐like growth factor‐1 (IGF‐1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti‐fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3‐MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF‐1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti‐fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.

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“…Wang et al . found that inhibition of mTORC1 ameliorated fibrosis in rat model of bile duct ligation 23. Li et al .…”

Section: Discussionmentioning

confidence: 98%

“…Growing researches show that mTOR pathway plays an important role in HSCs activation 22, 23, 24. Wang et al .…”

Section: Discussionmentioning

confidence: 99%

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Shi

Ren

Chen

et al. 2016

J Cellular Molecular Medi

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“…Meanwhile, the epithelial-mesenchymal transition (EMT), a major mechanism of tubulointerstitial fibrosis [11,12], is tightly associated with mTOR activity. Rapamycin (Rap), an mTOR signaling inhibitor, exerts an anti-fibrosis effect in many tissue fibrosis diseases [13,14,15]. However, whether Rap exerts a renoprotective effect in Aldo-induced renal injury has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Wang

Ding

Zhang

et al. 2015

Cell Physiol Biochem

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Background/Aim: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. Methods: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. Results: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. Conclusions: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.

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“…In rats with cirrhotic portal hypertension induced by bile duct ligation, mTOR was markedly activated and treatment with mTOR inhibitors decreased ALT, AST, alkaline phosphatase, intrahepatic neutrophils and lymphocytes and reduced TNF-α and inducible nitric oxide synthase mRNA expression. Moreover, reduction of fibrosis up to 70%, numbers of cholangiocytes and myo fibroblasts, and hepatic extracellular matrix deposition was observed [39,40]. Moreover, in post liver transplant patients, the use of mTOR inhibitors was associated with slower rate of liver fibrosis [41].…”

Section: Discussionmentioning

confidence: 99%

“…The relationship between mTOR and inflammation could be mutual where inflammatory cytokines such as TNF-α may activate mTOR [42] and mTOR promotes the expression of pro-inflammatory cytokines like TNF-α, IL-6, IL-1α and IL-1β [35,39,40]. In addition, mTOR activation enhances the expression of monocyte chemotactic protein-l and hepatic macrophage infiltration and polarization with M2 to M1 phenotype switch [43].…”

Section: Discussionmentioning

confidence: 99%

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

Lashen¹

2017

JLRDT

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Background: In chronic hepatitis C (CHC) infection, liver disease progression results from viral persistence. Deregulation of target of rapamycin (TOR) signaling and autophagy is detected in viral infections and cancer. We studied the role of TOR and autophagy in the progression of CHC infection.Methods: 54 patients infected with HCV, [27 with CHC; 13 with cirrhosis and 14 with hepatocellular carcinoma (HCC)]; and 15 healthy subjects were included. Quantification of serum TOR was determined using enzyme linked immunosorbent assay. Tissue samples were immune-stained using TOR and autophagy protein 5 (Atg5) polyclonal antibodies. Expression of TOR and Atg5 was scored semi-quantitatively.Results: Expression and serum TOR were higher in HCC patients compared to patients without HCC (P< 0.05). Serum and expression of TOR were positively correlated to inflammation, fibrosis, steatosis and tumor characteristics (Alpha-fetoprotein, maximum diameter, tumor grade and CLIP stage) (P<0.05). Expression of Atg5 was inversely correlated with inflammation, fibrosis and tumor characteristics (P<0.05), Atg5 showed significant inverse correlation with serum and intra-hepatic expression of TOR (P<0.05). Serum TOR showed high sensitivity and specificity in discriminating infected patients with and without HCC at a cut-off value of 4.55 ng/ml [Area under ROC curve = 0.970]. Conclusion:Activation of TOR plays an important role in progression of HCV related liver disease possibly though autophagy suppression and they could be a potential therapeutic target. Serum TOR is a potential seromarker in discriminating HCV infected patients with and without HCC with high sensitivity and specificity.

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Rapamycin Ameliorates Inflammation and Fibrosis in the Early Phase of Cirrhotic Portal Hypertension in Rats through Inhibition of mTORC1 but Not mTORC2

Cited by 51 publications

References 43 publications

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

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