• angiotensin‐(1–7)
• angiotensin‐converting enzyme 2
• clinical application
• liver disease
• renin‐angiotensin system

• 2025AFB479 Natural Science Foundation of Hubei Province
• 2024AFB140 Natural Science Foundation of Hubei Province
• WZ24B07 Funding for Scientific Research Projects from Wuhan Municipal Health Commission
• 82474130 National Natural Science Foundation of China
• 82074077 National Natural Science Foundation of China
• 32000278 National Natural Science Foundation of China

• cirrhotic portal hypertension
• endothelial dysfunction
• hyperdynamic circulation
• nitric oxide
• sinusoidal capillarization
• splanchnic vasodilation

• Beijing Municipal Natural Science Foundation

• Drug discovery
• Endothelial dysfunction
• Hemolysis
• Medicinal chemistry
• Nitric oxide
• Sickle cell anemia
• Vasculopathy

• Anemia, Sickle Cell/physiopathology
• Anemia, Sickle Cell/metabolism
• Anemia, Sickle Cell/complications
• Humans
• Endothelium, Vascular/metabolism
• Endothelium, Vascular/physiopathology
• Nitric Oxide/metabolism
• Animals
• Oxidative Stress
• Arginine/metabolism
• Arginine/analogs & derivatives

• ACE2
• acute liver injury
• apoptosis
• inflammation
• oxidative stress.
• sepsis

• Animals
• Angiotensin-Converting Enzyme 2/metabolism
• Sepsis/complications
• Sepsis/metabolism
• Angiotensin I/metabolism
• Receptors, G-Protein-Coupled/metabolism
• Mice
• Peptide Fragments/metabolism
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Mas
• Myeloid Cells/metabolism
• Apoptosis
• Mice, Knockout
• Oxidative Stress
• Peptidyl-Dipeptidase A/metabolism
• Mice, Transgenic
• Hepatocytes/metabolism
• Liver/pathology
• Liver/metabolism

• 82172123 National Natural Science Foundation of China

• Cardiac remodeling
• Cardiovascular disease
• Diabetes
• Renal disease
• Renin angiotensin aldosterone system
• SGLT-2

• Humans
• Heart Failure/drug therapy
• Heart Failure/physiopathology
• Neprilysin/antagonists & inhibitors
• Stroke Volume/drug effects
• Animals
• Angiotensin Receptor Antagonists/therapeutic use
• Angiotensin Receptor Antagonists/adverse effects
• Renin-Angiotensin System/drug effects

• AMPK/eNOS axis
• Alamandine
• MrgD
• Ovariectomy-induced osteoporosis
• Renin angiotensin system

• Mice
• Female
• Animals
• Rats
• Osteogenesis
• AMP-Activated Protein Kinases
• Nitric Oxide Synthase Type III
• X-Ray Microtomography
• Osteoporosis/drug therapy
• Osteoporosis/etiology
• Osteoporosis/prevention & control
• Oligopeptides

• QA2021005 Scientific Research Project of Nantong Commission of Health
• 81501913 National Natural Science Foundation of China
• M2021063 Scientific Research Project of Jiangsu Commission of Health
• BK20151275 Natural Science Foundation of Jiangsu Province

• CP: Cell biology
• cirrhosis
• hepatic stellate cell
• neprilysin
• neuropeptide Y
• neuropeptide Y receptor 1
• portal hypertension
• renin-angiotensin system

• Mice
• Humans
• Animals
• Neuropeptide Y
• Receptors, Neuropeptide Y
• Angiotensin-Converting Enzyme Inhibitors/pharmacology
• Neprilysin
• Angiotensin Receptor Antagonists
• Hypertension, Portal/drug therapy
• Fibrosis
• Liver Cirrhosis/drug therapy

• portal hypertension
• ascites
• liver

• Anoctamin-1
• Ca(2+)-activated Cl(-) channels
• Idiopathic Pulmonary Arterial Hypertension
• Portal Hypertension
• Systemic Hypertension
• TMEM16A
• Tone

Liver fibrosis is a wound-healing response that results from various chronic damages. If the causes of damage are not removed or effective treatments are not given in a timely manner, it will progress to cirrhosis, even liver cancer. Currently, there are no specific medical therapies for liver fibrosis. Adeno-associated virus (AAV)-mediated gene therapy, one of the frontiers of modern medicine, has gained more attention in many fields due to its high safety profile, low immunogenicity, long-term efficacy in mediating gene expression, and increasingly known tropism. Notably, increasing evidence suggests a promising therapeutic potential for AAV-mediated gene therapy in different liver fibrosis models, which helps to correct abnormally changed target genes in the process of fibrosis and improve liver fibrosis at the molecular level. Moreover, the addition of cell-specific promoters to the genome of recombinant AAV helps to limit gene expression in specific cells, thereby producing better therapeutic efficacy in liver fibrosis. However, animal models are considered to be powerless predictive of tissue tropism, immunogenicity, and genotoxic risks in humans. Thus, AAV-mediated gene therapy will face many challenges. This review systemically summarizes the recent advances of AAV-mediated gene therapy in liver fibrosis, especially focusing on cellular and molecular mechanisms of transferred genes, and presents prospective challenges.

• AAV
• HSCs
• cellular mechanism
• gene therapy
• liver fibrosis

• ACE2
• AT2R
• AT2R agonist
• Angiotensin-(1-9)
• Hypertension

Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) – a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.

• TMEM16A
• angiotensin II
• bilirubin
• calcium-activated chloride channel
• cirrhosis
• portal hypertension
• portal vein
• smooth muscle

• angiotensin receptor blocker
• hepatic stellate cells
• hydrostatic pressure
• liver fibrosis
• mechanotransduction

Hypertensive renal injury is a complication of hypertension. Cordyceps cicadae (C. cicadae) is a traditional Chinese medicine used to treat chronic kidney diseases especially renal fibrosis. Autophagy is described as a cell self-renewal process that requires lysosomal degradation and is utilized for the maintenance of cellular energy homeostasis. The present study explores the mechanism underlying C. cicadae’s renoprotection on hypertensive nephropathy (HN). First, HN rat models were established on spontaneously hypertensive rats (SHRs). The expression of fibrosis-related protein and autophagy-associated protein was detected in vivo. NRK-52E cells exposed to AngII were chosen to observe the potential health benefits of C. cicadae on renal damage. The level of extracellular matrix accumulation was detected using capillary electrophoresis immunoquantification and immunohistochemistry. After treatment with lysosomal inhibitors (chloroquine) or an autophagy activator (rapamycin), the expression of Beclin-1, LC3II, and SQSTM1/p62 was further investigated. The study also investigated the change in sirtuin1 (SIRT1), fork head box O3a (FOXO3a), and peroxidation (superoxide dismutase (SOD) and malondialdehyde (MDA)) expression when intervened by resveratrol. The changes in SIRT1 and FOXO3a were measured in patients and the SHRs. Here, we observed that C. cicadae significantly decreased damage to renal tubular epithelial cells and TGFβ1, α-smooth muscle actin (α-SMA), collagen I (Col-1), and fibronectin expression. Meanwhile, autophagy defects were observed both in vivo and in vitro. C. cicadae intervention significantly downregulated Beclin-1 and LC3II and decreased SQSTM1/p62, showing an inhibition of autophagic vesicles and the alleviation of autophagy stress. These functions were suppressed by rapamycin, and the results were just as effective as the resveratrol treatment. HN patients and the SHRs exhibited decreased levels of SIRT1 and FOXO3a. We also observed a positive correlation between SIRT1/FOXO3a and antifibrotic effects. Similar to the resveratrol group, the expression of SIRT1/FOXO3a and oxidative stress were elevated by C. cicadae in vivo. Taken together, our findings show that C. cicadae ameliorates tubulointerstitial fibrosis and delays HN progression. Renoprotection was likely attributable to the regulation of autophagic stress mediated by the SIRT1 pathway and achieved by regulating FOXO3a and oxidative stress.

Introduction  An array of routinely accessible serum biomarkers was assessed to explore their overall impact on severity and mortality in coronavirus disease 2019.

Materials and Methods  A retrospective analysis of 1,233 adults was conducted. The study groups comprised 127 nonsurvivors and 1,106 survivors. Data for demographic details, clinical presentations, and laboratory reports were recorded from the medical record section. The predictors were analyzed for their influence on mortality.

Results  The mean (+ standard deviation) age of the patients in the nonsurvivor group was 58.8 (13.8) years. The mean age (56.4 years) was highest in severe grade patients. The odds ratio for death was 2.72 times for patients above the age of 40 years. About 46% of nonsurvivors died within 5 days of admission. Males were found to be more prone to death than females by a factor of 1.36. Serum urea depicted highest sensitivity (85%) for nonsurvival at 52.5 mg/dL. Serum albumin (3.23 g/dL), albumin-to-globulin ratio (0.97), and C-reactive protein-to albumin ratio (CAR) (2.08) showed a sensitivity of more than 70% for mortality outcomes. The high hazard ratio (HR) for deceased patients with hyperkalemia was 2.419 (95% confidence interval [CI] = 1.96–2.99; p  < 0.001). The risk for nonsurvival was increased with elevated serum creatinine by 15.6% and uric acid by 21.7% ( p  < 0.001). The HR for hypoalbuminemia was 0.254 (95% CI: 0.196–0.33; p  < 0.001) and CAR was 1.319 (95% CI: 1.246–1.397; p  < 0.001). Saturation of oxygen ( p  < 0.001), lactate dehydrogenase ( p  = 0.006), ferritin ( p  = 0.004), hyperuricemia ( p  = 0.027), hyperkalemia ( p  < 0.001), hypoalbuminemia ( p  = 0.002), and high CAR values (0.031) served as potential predictors for mortality.

Conclusion  Adjusting for all the predictor variables, serum uric acid, potassium, albumin, and CAR values at the time of admission were affirmed as the potential biomarkers for mortality.

• ALT, alanine aminotransferase
• ARB, angiotensin receptor blocker
• AST, aspartate aminotransferase
• ATII, angiotensin II
• COX, cyclooxygenase
• ET, endothelin
• HFHFD, high-fat high-fructose diet
• IHVR, intrahepatic vascular resistance
• Jak2, Janus-kinase-2
• MCD, methionine-choline deficient diet
• Mx, methoxamine
• NAFLD, non-alcoholic fatty liver disease
• NASH, non-alcoholic steatohepatitis
• NO, nitric oxide
• PP, portal pressure
• PR, pulse rate
• SEM, scanning electron microscopy
• TBW, total body weight
• TEM, transmission electron microscopy
• TXAS, thromboxane synthase
• TxA2, thromboxane A2
• ZFR, Zucker fatty rats
• angiotensin II
• endothelin-1
• non-alcoholic fatty liver disease
• portal hypertension
• thromboxane A2
• transhepatic pressure gradient

• Alzheimer’s disease
• amyloid-beta precursor protein
• angiotensin-converting enzyme-2
• coronavirus-2019
• meta-analysis
• severe acute respiratory syndrome-coronavirus-2

• Amyloid beta-Protein Precursor/genetics
• Amyloid beta-Protein Precursor/metabolism
• Angiotensin-Converting Enzyme 2/genetics
• Angiotensin-Converting Enzyme 2/metabolism
• COVID-19/genetics
• COVID-19/metabolism
• COVID-19/pathology
• Gene Expression Regulation
• Humans
• Plaque, Amyloid/genetics
• Plaque, Amyloid/metabolism
• Plaque, Amyloid/pathology
• SARS-CoV-2/metabolism
• SARS-CoV-2/pathogenicity
• SARS-CoV-2/physiology
• Signal Transduction/genetics

• DA046258 NIH HHS

• Angiotensin II
• Chinese population
• LCMS
• Reference intervals

• COVID-19
• coronavirus
• drug hepatotoxicity
• liver diseases
• liver injury

• COVID-19
• Liver function tests
• SARS-CoV-2

• Alanine Transaminase
• Aspartate Aminotransferases
• COVID-19/complications
• Humans
• L-Lactate Dehydrogenase
• Liver/enzymology
• Liver Diseases/epidemiology
• Liver Diseases/virology
• Liver Function Tests

• Angiotensin converting enzyme 2
• COVID-19
• Chronic liver disease
• Clinical outcome
• Common medications
• Hepatobiliary tissue
• SARS-CoV-2

• ACE2
• COVID-19
• SARS-CoV-2
• diabetes
• energy homeostasis
• renin-angiotensin system

There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1–7) (Ang-(1–7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS.

• Mas related G protein-coupled receptor type-D
• angiotensin converting enzyme 2
• angiotensin-(1–7)
• liver fibrosis and cirrhosis
• portal hypertension
• renin angiotensin system

• angiotensin receptor blockers
• angiotensin-converting enzyme inhibitors
• cardiac surgery
• liver cirrhosis

• Adrenergic beta-Antagonists/administration & dosage
• Adrenergic beta-Antagonists/adverse effects
• Aged
• Aged, 80 and over
• Angiotensin Receptor Antagonists/administration & dosage
• Angiotensin Receptor Antagonists/adverse effects
• Angiotensin-Converting Enzyme Inhibitors/administration & dosage
• Angiotensin-Converting Enzyme Inhibitors/adverse effects
• Cardiac Surgical Procedures/statistics & numerical data
• Cardiovascular Agents/administration & dosage
• Cardiovascular Agents/adverse effects
• Cardiovascular Agents/classification
• Female
• Humans
• Hypoglycemic Agents/administration & dosage
• Hypoglycemic Agents/adverse effects
• Liver Cirrhosis/epidemiology
• Male
• Middle Aged
• Renal Insufficiency/epidemiology
• Taiwan/epidemiology

• diseases
• infectious diseases

• Aged
• COVID-19/epidemiology
• Comorbidity
• Female
• Humans
• Iran/epidemiology
• Liver Diseases/complications
• Liver Diseases/epidemiology
• Male
• Middle Aged
• Retrospective Studies
• Risk Factors
• Severity of Illness Index

• Cardiovascular Diseases/complications
• Cardiovascular Diseases/physiopathology
• Chronic Disease
• Humans
• Inflammation/physiopathology
• Liver Diseases/complications
• Liver Diseases/physiopathology
• Oxidative Stress/physiology

• 1ZIAAA000375-13 NIAAA NIH HHS

• COVID-19
• SARS-CoV-2
• angiotensin converting enzyme 2
• cirrhosis
• protective RAS
• renin-angiotensin system

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

• Portal hypertension
• Cirrhosis
• Intrahepatic vascular resistance
• Hyperdynamic circulatory state
• Splanchnic vasodilatation
• Portal blood flow
• Non-selective beta-blockers
• Alternate renin angiotensin system

• Esophageal and Gastric Varices
• Gastrointestinal Hemorrhage
• Humans
• Hypertension, Portal/drug therapy
• Hypertension, Portal/etiology
• Liver Cirrhosis/complications
• Liver Cirrhosis/drug therapy
• Portal Pressure

• Angiotensin II/metabolism
• Angiotensin-Converting Enzyme 2
• Apoptosis
• Betacoronavirus/pathogenicity
• Betacoronavirus/physiology
• COVID-19
• Comorbidity
• Coronavirus Infections/metabolism
• Coronavirus Infections/mortality
• Coronavirus Infections/physiopathology
• Disease Progression
• Disease Susceptibility
• Humans
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/metabolism
• Pandemics
• Peptidyl-Dipeptidase A/metabolism
• Pneumonia, Viral/metabolism
• Pneumonia, Viral/mortality
• Pneumonia, Viral/physiopathology
• Preliminary Data
• SARS-CoV-2
• Up-Regulation

• COVID-19
• SARS-CoV-2
• Wuhan
• clinical significance
• liver function

The kidney is innervated by afferent sensory and efferent sympathetic nerve fibers. Norepinephrine (NE) is the primary neurotransmitter for post-ganglionic sympathetic adrenergic nerves, and its signaling, regulated through adrenergic receptors (AR), modulates renal function and pathophysiology under disease conditions. Renal sympathetic overactivity and increased NE level are commonly seen in chronic kidney disease (CKD) and are critical factors in the progression of renal disease. Blockade of sympathetic nerve-derived signaling by renal denervation or AR blockade in clinical and experimental studies demonstrates that renal nerves and its downstream signaling contribute to progression of acute kidney injury (AKI) to CKD and fibrogenesis. This review summarizes our current knowledge of the role of renal sympathetic nerve and adrenergic receptors in AKI, AKI to CKD transition and CKDand provides new insights into the therapeutic potential of intervening in its signaling pathways.

• acute kidney injury
• adrenergic receptor
• chronic kidney disease
• norepinephrine
• sympathetic nervous system

• Acute Kidney Injury/metabolism
• Animals
• Humans
• Kidney/innervation
• Receptors, Adrenergic/metabolism
• Renal Insufficiency, Chronic/metabolism
• Signal Transduction
• Sympathetic Nervous System/metabolism

• DK-116987 NIH HHS
• DK-120533 NIH HHS
• DK 120846 NIH HHS
• R01 DK116987 NIDDK NIH HHS
• R01 DK120846 NIDDK NIH HHS

• Aged
• Betacoronavirus/pathogenicity
• COVID-19
• Coronavirus Infections/physiopathology
• Coronavirus Infections/virology
• Humans
• Pandemics
• Pneumonia, Viral/physiopathology
• Pneumonia, Viral/virology
• Renin-Angiotensin System/physiology
• SARS-CoV-2

There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang‐(1‐7). In the present study, we investigated long‐term effects of ACE2 delivered by an adeno‐associated viral vector and short‐term effects of Ang‐(1‐7) peptide in multiple drug‐resistant gene 2‐knockout (Mdr2‐KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P < 0.05) and biliary fibrosis (P < 0.01) at both established (3‐6 months of age) and advanced (7‐9 months of age) disease compared to control vector‐injected Mdr2‐KO mice. This was accompanied by increased hepatic Ang‐(1‐7) levels (P < 0.05) with concomitant reduction in hepatic Ang II levels (P < 0.05) compared to controls. Moreover, Ang‐(1‐7) peptide infusion improved liver injury (P < 0.05) and biliary fibrosis (P < 0.0001) compared to saline‐infused disease controls. The therapeutic effects of both ACE2 therapy and Ang‐(1‐7) infusion were associated with significant (P < 0.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and/or cholangiocytes in vivo, Ang‐(1‐7) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen‐secreting myofibroblastic phenotype in vitro. We showed that an increased ratio of hepatic Ang‐(1‐7) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. Conclusion: ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.

• ACEI
• ARB
• Arthritis
• Bone
• Osteoporosis
• Renin-angiotensin system

• Animals
• Bone Diseases/drug therapy
• Bone Diseases/metabolism
• Bone and Bones/metabolism
• Humans
• Renin-Angiotensin System

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.

• cirrhosis
• portal hypertension
• renin-angiotensin system

Chronic liver diseases that inevitably lead to hepatic fibrosis, cirrhosis and/or hepatocellular carcinoma have become a major cause of illness and death worldwide. Among them, cholangiopathies or cholestatic liver diseases comprise a large group of conditions in which injury is primarily focused on the biliary system. These include congenital diseases (such as biliary atresia and cystic fibrosis), acquired diseases (such as primary sclerosing cholangitis and primary biliary cirrhosis), and those that arise from secondary damage to the biliary tree from obstruction, cholangitis or ischaemia. These conditions are associated with a specific pattern of chronic liver injury centered on damaged bile ducts that drive the development of peribiliary fibrosis and, ultimately, biliary cirrhosis and liver failure. For most, there is no established medical therapy and, hence, these diseases remain one of the most important indications for liver transplantation. As a result, there is a major need to develop new therapies that can prevent the development of chronic biliary injury and fibrosis. This mini-review briefly discusses the pathophysiology of liver fibrosis and its progression to cirrhosis. We make a special emphasis on biliary fibrosis and current therapeutic options, such as angiotensin converting enzyme-2 (known as ACE2) over-expression in the diseased liver as a novel potential therapy to treat this condition.

• Chronic liver disease
• Biliary fibrosis
• Current therapies for biliary fibrosis
• Angiotensin converting enzyme-2
• Gene therapy

The discovery that renin–angiotensin system (RAS) components are locally expressed in the liver tissue, pointed out to a role for this system in the pathogenesis of hepatic fibrosis and cirrhosis. The RAS counter-regulatory axis composed by the angiotensin converting enzyme 2 (ACE2), angiotensin-(1-7) [Ang-(1-7)] and Mas receptor mediates pro-inflammatory, pro-thrombotic, and pro-fibrotic processes, frequently opposing the classical RAS arm (ACE-Ang II-AT₁ receptor) actions. Therefore, the balance between both RAS axes most likely affects the clinical and histopathological expression of liver diseases. It is worth noticing that liver diseases are major causes of morbidity and mortality worldwide. Without proper treatment, all types of chronic hepatitis will progress to end-stage liver diseases, including cirrhosis, liver failure, and hepatocellular carcinoma, which ultimately lead to death. In this context, to better comprehend the role of RAS components in liver failure might pave the way for the search of potential predictive biomarkers as well as the development of novel therapeutic approaches. Valuable data have been generated from preclinical and clinical studies. Herein, we summarize the current evidence, mainly focusing in the ACE2-Ang-(1-7)-Mas receptor arm, regarding the role of RAS in liver diseases. The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.

• Angiotensin II receptor blockers
• Cirrhosis
• Meta-analysis
• Portal hypertension

• Angiotensin Receptor Antagonists/pharmacology
• Angiotensin Receptor Antagonists/therapeutic use
• Antihypertensive Agents/pharmacology
• Antihypertensive Agents/therapeutic use
• Humans
• Hypertension, Portal/drug therapy
• Hypertension, Portal/pathology
• Hypotension/chemically induced
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Randomized Controlled Trials as Topic

Liver cirrhosis is characterized by avid sodium retention where the activation of the renin angiotensin aldosterone system (RAAS) is considered to be the hallmark of the sodium retaining mechanisms. The direct effect of angiotensin II (ANGII) on the AT-1 receptor in the proximal tubules is partly responsible for the sodium retention. The aim was to estimate the natriuretic and neurohumoral effects of an ANGII receptor antagonist (losartan) in the late phase of the disease in a rat model of liver cirrhosis.

Bile duct ligated (BDL) and sham operated rats received 2 weeks of treatment with losartan 4 mg/kg/day or placebo, given by gastric gavage 5 weeks after surgery. Daily sodium and potassium intakes and renal excretions were measured.

The renal sodium excretion decreased in the BDL animals and this was not affected by losartan treatment. At baseline the plasma renin concentration (PRC) was similar in sham and BDL animals, but increased urinary excretion of ANGII and an increase P-Aldosterone was observed in the placebo treated BDL animals. The PRC was more than 150 times higher in the losartan treated BDL animals (p < 0.001) which indicated hemodynamic impairment.

Losartan 4 mg/kg/day did not increase renal sodium excretion in this model of liver cirrhosis, although the urinary ANGII excretion was increased. The BDL animals tolerated Losartan poorly, and the treatment induced a 150 times higher PRC.

• ANGII antagonists
• Aldosterone
• Bile duct ligation
• Liver cirrhosis
• Sodium retention

• Adult congenital heart disease
• Fontan

• Aliskiren
• Hepatic stellate cell
• Lisinopril
• Liver fibrosis
• Losartan
• Schistosomiasis

• Angiotensins
• Hepatic fibrosis
• Hypertension, portal
• Receptors, angiotensin
• Renin-angiotensin system

• Angiotensin II
• Angiotensin-Converting Enzyme Inhibitors
• Humans
• Hypertension, Portal/metabolism
• Liver Cirrhosis/metabolism
• Peptide Fragments
• Renin-Angiotensin System

• Biejiajian Oral Liquid
• Chinese medicine
• carbon tetrachloride
• hepatic fibrosis
• renin-angiotensin-aldosterone system

• brain natriuretic peptide (BNP)
• hyponatremia
• liver cirrhosis
• tolvaptan

• Aged
• Antidiuretic Hormone Receptor Antagonists/therapeutic use
• Ascites/complications
• Benzazepines/therapeutic use
• Female
• Humans
• Hyponatremia/complications
• Hyponatremia/drug therapy
• Japan
• Liver Cirrhosis/complications
• Male
• Middle Aged
• Prognosis
• Retrospective Studies
• Sodium/blood
• Tolvaptan
• Treatment Outcome