Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases

Taşkın, Eylem; Güven, Cengiz

doi:10.5772/65919

Cited by 8 publications

(10 citation statements)

References 48 publications

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“…The circulating renin-angiotensin system (RAS) is mainly known for its vital function in maintaining cardiovascular homeostasis, electrolyte balance and kidney function [ 55 ]. Angiotensin I (Ang I), angiotensin II (Ang II), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin (Ang) are considered essential elements of the RAS system [ 56 , 57 ]. Interestingly, previous studies suggest that RAS is involved in the formation and development of LIHC [ 56 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

Yan

Niu

et al. 2022

J Transl Med

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Background Liver hepatocellular carcinoma (LIHC) ranks sixth among the most common types of cancer with a high mortality rate. Cuproptosis is a newly discovered type of cell death in tumor, which is characterized by accumulation of intracellular copper leading to the aggregation of mitochondrial lipoproteins and destabilization of proteins. Thus, understanding the exact effects of cuproptosis-related genes in LIHC and determining their prognosticvalue is critical. However, the prognostic model of LIHC based on cuproptosis-related genes has not been reported. Methods Firstly, we downloaded transcriptome data and clinical information of LIHC patients from TCGA and GEO (GSE76427), respectively. We then extracted the expression of cuproptosis-related genes and established a prognostic model by lasso cox regression analysis. Afterwards, the prediction performance of the model was evaluated by Kaplan–Meier survival analysis and receiver operating characteristic curve (ROC). Then, the prognostic model and the expression levels of the three genes were validated using the dataset from GEO. Subsequently, we divided LIHC patients into two subtypes by non-negative matrix factorization (NMF) classification and performed survival analysis. We constructed a Sankey plot linking different subtypes and prognostic models. Next, we calculate the drug sensitivity of each sample from patients in the high-risk group and low-risk group by the R package pRRophetic. Finally, we verified the function of LIPT1 in LIHC. Results Using lasso cox regression analysis, we developed a prognostic risk model based on three cuproptosis-related genes (GCSH, LIPT1 and CDKN2A). Both in the training and in the test sets, the overall survival (OS) of LIHC patients in the low-risk group was significantly longer than that in the high-risk group. By performing NMF cluster, we identified two molecular subtypes of LIHC (C1 and C2), with C1 subtype having significantly longer OS and PFS than C2 subtype. The ROC analysis indicated that our model had a precisely predictive capacity for patients with LIHC. The multivariate Cox regression analysis indicated that the risk score is an independent predictor. Subsequently, we identified 71 compounds with IC50 values that differed between the high-risk and low-risk groups. Finally, we determined that knockdown of LIPT1 gene expression inhibited proliferation and invasion of hepatoma cells. Conclusion In this study, we developed a novel prognostic model for hepatocellular carcinoma based on cuproptosis-related genes that can effectively predict the prognosis of LIHC patients. The model may be helpful for clinicians to make clinical decisions for patients with LIHC and provide valuable insights for individualized treatment. Two distinct subtypes of LIHC were identified based on cuproptosis-related genes, with different prognosis and immune characteristics. In addition, we verified that LIPT1 may promote proliferation, invasion and migration of LIHC cells. LIPT1 might be a new potential target for therapy of LIHC.

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Section: Discussionmentioning

confidence: 99%

System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

Yan

Niu

et al. 2022

J Transl Med

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“…It has been described that the liver presents a local RAS 50 and that the major effector peptide of the system, Ang II, can be secreted by activated hepatic stellate cells and plays an important role in amplifying oxidative stress in the organ 14,15 . Investigating these local RAS components, our analysis shows that Ang II is increased in diabetic mice and S. boulardii reduced the hepatic concentration of this peptide to the control level.…”

Section: Discussionmentioning

confidence: 99%

“…Based on these data, we concluded that as long as hyperglycemia and the consequent increased oxidative stress lead to hepatic cells apoptosis and necrosis, hypertrophy in the diabetic group is occurring as a compensatory mechanism for organ mass loss. Besides that, as the angiotensin generated peptide fragments are also associated with cell growth, cell proliferation, and apoptosis 14,58 , the increased level of Ang II in the liver as well as the prolonged stimulation of the system, are contributing to the abnormal cell growth 59,60 .…”

Section: Discussionmentioning

confidence: 99%

Saccharomyces boulardii modulates oxidative stress and renin angiotensin system attenuating diabetes-induced liver injury in mice

Barssotti

Abreu

Brandão

et al. 2021

Sci Rep

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Type 1 diabetes (T1DM) is a chronic disease characterized by hyperglycemia due to a deficiency in endogenous insulin production, resulting from pancreatic beta cell death. Persistent hyperglycemia leads to enhanced oxidative stress and liver injury. Several studies have evaluated the anti-diabetic and protective effects of probiotic strains in animal models. In the present study, we investigated, through histopathological and biochemical analyses, the effects of eight weeks of administration of Saccharomyces boulardii (S. boulardii) yeast on the liver of streptozotocin (STZ) induced diabetic C57BL/6 mice. Our results demonstrated that S. boulardii attenuates hepatocytes hydropic degeneration and hepatic vessels congestion in STZ-induced diabetic mice. The treatment attenuated the oxidative stress in diabetic mice leading to a reduction of carbonylated protein concentration and increased activity of antioxidant enzymes superoxide dismutase and glutathione peroxidase, compared to untreated diabetic animals. The results also show the beneficial influence of S. boulardii in regulating the hepatic concentration of renin angiotensin system (RAS) peptides. Therefore, our results demonstrated that S. boulardii administration to STZ-induced diabetic mice reduces oxidative stress and normalizes the concentration of RAS peptides, supporting the hypothesis that this yeast may have a role as a potential adjunctive therapy to attenuate diabetes-induced liver injury.

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“…The liver is a highly specialized tissue consisting of mostly hepatocytes that process and detoxify various metabolites, synthesize proteins and regulate a wide variety of biochemical reactions necessary for digestion and general metabolism. The liver is thought to be responsible for up to 500 separate functions, usually in combination with other systems and organs, and it has a remarkable great regeneration capability against injury [ 9 ].…”

Section: Metabolic Role Of Liver In Lipid and Carbohydrate Metabolismmentioning

confidence: 99%

“…The liver is the primary source of angiotensinogen for central RAS in the circulation [ 3 , 14 , 16 ]. According to one study, angiotensin II is mainly produced by hepatic Kupffer’s cells and hepatocytes [ 9 ]. In addition, the renin gene has been identified in hepatocytes [ 17 ] but its expression appears to be specifically repressed in vivo [ 18 ]; thus, its biological role as potential activator of the pro-renin receptor remains to be elucidated [ 18 ].…”

Section: Local Hepatic Rasmentioning

confidence: 99%

Renin–Angiotensin System in Liver Metabolism: Gender Differences and Role of Incretins

et al. 2022

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The impaired hepatic lipids and carbohydrates metabolism result in various metabolic disorders, including obesity, diabetes, insulin resistance, hyperlipidemia and metabolic syndrome. The renin–angiotensin system (RAS) has been identified in the liver and it is now recognized as an important modulator of body metabolic processes. This review is intended to provide an update of the impact of the renin–angiotensin system on lipid and carbohydrate metabolism, regarding gender difference and prenatal undernutrition, specifically focused on the role of the liver. The discovery of angiotensin-converting enzyme 2 (ACE2) has renewed interest in the potential therapeutic role of RAS modulation. RAS is over activated in non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma. Glucagon-like peptide-1 (GLP-1) has been shown to modulate RAS. The GLP-I analogue liraglutide antagonizes hepatocellular steatosis and exhibits liver protection. Liraglutide has a negative effect on the ACE/AngII/AT1R axis and a positive impact on the ACE2/Ang(1-7)/Mas axis. Activation of the ACE2/Ang(1-7)/Mas counter-regulatory axis is able to prevent liver injuries. Angiotensin(1-7) and ACE2 shows more favorable effects on lipid homeostasis in males but there is a need to do more investigation in female models. Prenatal undernutrition exerts long-term effects in the liver of offspring and is associated with a number of metabolic and endocrine alterations. These findings provide a novel therapeutic regimen to prevent and treat many chronic diseases by accelerating the effect of the ACE2/Ang1-7/Mas axis and inhibiting the ACE/AngII/AT1R axis.

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Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases

Cited by 8 publications

References 48 publications

System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

Saccharomyces boulardii modulates oxidative stress and renin angiotensin system attenuating diabetes-induced liver injury in mice

Renin–Angiotensin System in Liver Metabolism: Gender Differences and Role of Incretins

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