This study aims to investigate the effects of renin inhibitor aliskiren on kidney injury in human angiotensinogen-renin (AGT-REN) double transgenic hypertensive (dTH) mice and explore its possible mechanism. The dTH mice were divided into hypertension group (HT group) and aliskiren intervention group (HT+Aliskiren group), while wild-type C57BL/6 mice were served as the control group (WT group). Blood pressure data of mice in HT+Aliskiren group were collected after 28 d of subcutaneous penetration of aliskiren (20 mg/kg), and the damage of renal tissue structure and collagen deposition were observed by HE, Masson and PAS staining. The ultrastructure of kidney was observed by transmission electron microscope. Coomassie bright blue staining and biochemical analyzer were used to detect renal function injury. The expression of renin-angiotensin system (RAS) was determined by ELISA and immunohistochemistry. The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in kidney were determined by chemiluminescence method. The content of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47^phox, inducible nitric oxide synthase (iNOS), 3-nitrotyrosine (3-NT), NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) were detected by Western blot analysis. The results showed that compared with WT group, the blood pressure of mice in HT group was significantly increased. The renal tissue structure in HT group showed glomerular sclerosis, severe interstitial tubular injury, and increased collagen deposition. In addition, 24 h urinary protein, serum creatinine and urea levels increased. Serum and renal tissue levels of angiotensin II (Ang II) were increased, serum angiotensin-(1-7) [Ang-(1-7)] expression was decreased, and renal Ang-(1-7) expression was elevated. The expressions of ACE, Ang II type 1 receptor (AT₁R) and MasR in renal tissue were increased, while the expression of ACE2 was decreased. MDA content increased, SOD content decreased, and the expressions of p47^phox, iNOS, 3-NT, NOX2 and NOX4 were increased. However, aliskiren reduced blood pressure in dTH mice, improved renal structure and renal function, reduced Ang II and Ang-(1-7) levels in serum and renal tissue, reduced the expression of ACE and AT₁R in renal tissue, increased the expression of ACE2 and MasR in renal tissue, and decreased the above levels of oxidative stress indexes in dTH mice. These results suggest that aliskiren may play a protective role in hypertensive renal injury by regulating the balance between ACE-Ang II-AT₁R and ACE2-Ang-(1-7)-MasR axes and inhibiting oxidative stress.
Animals ; Fumarates/therapeutic use* ; Mice ; Renin/antagonists & inhibitors* ; Amides/therapeutic use* ; Mice, Inbred C57BL ; Hypertension/physiopathology* ; Mice, Transgenic ; Kidney/pathology* ; Angiotensinogen/genetics* ; Renin-Angiotensin System/drug effects* ; NADPH Oxidases/metabolism* ; Male ; Antihypertensive Agents/pharmacology* ; Humans ; Superoxide Dismutase/metabolism* ; NADPH Oxidase 4

Consecutively hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) in Wuhan, China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin-angiotensin system inhibitor (RAS-I) and the outcome of this disease. Associations between the use of RAS-I (angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)), ACEI, and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status. A total of 2771 patients with COVID-19 were included, with moderate and severe cases accounting for 45.0% and 36.5%, respectively. A total of 195 (7.0%) patients died. RAS-I (hazard ratio (HR)= 0.499, 95% confidence interval (CI) 0.325-0.767) and ARB (HR = 0.410, 95% CI 0.240-0.700) use was associated with a reduced risk of all-cause mortality among patients with COVID-19. For patients with hypertension, RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352 (95% CI 0.162-0.764) and 0.279 (95% CI 0.115-0.677), respectively. RAS-I exhibited protective effects on the survival outcome of COVID-19. ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.
Angiotensin Receptor Antagonists/therapeutic use* ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use* ; COVID-19 ; Humans ; Hypertension/drug therapy* ; Renin-Angiotensin System ; Retrospective Studies

OBJECTIVE: Cardiovascular diseases are associated with an increased risk of depression, but it remains unclear whether treatment with cardiovascular agents decreases or increases this risk. The effects of drugs on individual usage are also often unknown. This review aimed to examine the correlation between depression and common cardiovascular drugs, develop more potent interventions for depression in cardiovascular patients, and further research on the bio-behavioural mechanisms linking cardiovascular drugs to depression. DATA SOURCES: The data in this review were obtained from articles included in PubMed, EMBASE, and Web of Science. STUDY SELECTION: Clinical trials, observational studies, review literature, and guidelines about depression and cardiovascular drugs were selected for the article. RESULTS: We systematically investigated whether the seven most used cardiovascular drugs were associated with altered risk of incident depression in this literature review. Statins have been proven to have antidepressant effects. Some studies believe angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARB) can exert an antidepressant influence by acting on the renin-angiotensin system, but further clinical trials are needed to confirm this. Beta-blockers have previously been associated with depression, but the current study found no significant association between beta blockers and the risk of depression. Aspirin may have antidepressant effects by suppressing the immune response, but its role as an antidepressant remains controversial. calcium channel blockers (CCBs) can regulate nerve signal transduction by adjusting calcium channels, but whether this effect is beneficial or harmful to depression remains unclear. Finally, some cases have reported that nitrates and diuretics are associated with depression, but the current clinical evidence is insufficient. CONCLUSIONS Statins have been proven to have antidepressant effect, and the antidepressant effects of ACEIs/ARB and aspirin are still controversial. CCBs are associated with depression, but it is unclear whether it is beneficial or harmful. No association has been found with β-blockers, diuretics, and nitrates.
Angiotensin Receptor Antagonists/therapeutic use* ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use* ; Antihypertensive Agents/therapeutic use* ; Calcium Channel Blockers/therapeutic use* ; Cardiovascular Agents/therapeutic use* ; Cardiovascular Diseases/drug therapy* ; Depression/drug therapy* ; Humans ; Hypertension/drug therapy* ; Renin-Angiotensin System

Angiotensin Receptor Antagonists ; therapeutic use ; Betacoronavirus ; Cardiovascular Diseases ; complications ; drug therapy ; Coronavirus Infections ; complications ; Humans ; Pandemics ; Pneumonia, Viral ; complications ; Renin-Angiotensin System ; drug effects

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1–7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1–7)/Mas receptor and ACE2/Ang-(1–9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.
Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Cell Proliferation ; Fibrosis* ; Hemodynamics ; Humans ; Hypertension, Portal* ; Inflammation ; Liver Cirrhosis ; Mineralocorticoid Receptor Antagonists ; Receptors, Angiotensin ; Renin-Angiotensin System* ; Sodium ; Vasoconstriction ; Vasodilation

BACKGROUND: Acute respiratory distress syndrome (ARDS) remains a life-threatening disease. Many patients with ARDS do not recover fully, and progress to terminal lung fibrosis. Angiotensin-converting enzyme (ACE) inhibitor is known to modulate the neurohormonal system to reduce inflammation and to prevent tissue fibrosis. However, the role of ACE inhibitor in the lungs is not well understood. We therefore conducted this study to elucidate the effect of renin-angiotensin system (RAS) blockage on the prognosis of patients with ARDS. METHODS: We analyzed medical records of patients who were admitted to the medical intensive care unit (ICU) at a tertiary care hospital from January 2005 to December 2010. ARDS was determined using the Berlin definition. The primary outcome was the mortality rate of ICU. Survival analysis was performed after adjustment using propensity score matching. RESULTS: A total of 182 patients were included in the study. Thirty-seven patients (20.3%) took ACE inhibitor or angiotensin receptor blocker (ARB) during ICU admission, and 145 (79.7%) did not; both groups showed similar severity scores. In the ICU, mortality was 45.9% in the RAS inhibitor group and 58.6% in the non-RAS inhibitor group (P = 0.166). The RAS inhibitor group required a longer duration of mechanical ventilation (29.5 vs. 19.5, P = 0.013) and longer ICU stay (32.1 vs. 20.2 days, P < 0.001). In survival analysis, the RAS inhibitor group showed better survival rates than the non-RAS group (P < 0.001). CONCLUSIONS: ACE inhibitor or ARB may have beneficial effect on ARDS patients.
Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Berlin ; Case-Control Studies* ; Fibrosis ; Humans ; Inflammation ; Intensive Care Units ; Lung ; Medical Records ; Mortality ; Prognosis ; Propensity Score ; Renin-Angiotensin System* ; Respiration, Artificial ; Respiratory Distress Syndrome, Adult* ; Retrospective Studies* ; Survival Rate ; Tertiary Healthcare

INTRODUCTION: Anthracycline is a cornerstone in the treatment of various cancers. One major limitation to its use is cardiotoxicity. Renin angiotensin system (RAS) inhibitors have been shown to attenuate myocardial injury, initial data is promising in its use as prophylaxis for anthracyclineinduced cardiotoxicity. The aim of the study is to determine effectiveness of prophylactic RAS inhibitors in preventing anthracycline-induced cardiotoxicity and adverse cardiac events among adult cancer patients

METHODS: Systematic search of databases PUBMED, MEDLINE, EMBASE, and CENTRAL was done. Selection criteria were: 1) randomized controlled trials (RCT) 2) adult cancer patients with normal ejection fraction and without heart failure symptoms 3) RAS inhibitors as prophylaxis versus placebo 4) development of cardiac events, all-cause mortality and left ventricular ejection fraction (LVEF) reduction as outcomes. Two reviewers independently assessed the trials. Disagreements were resolved with a third reviewer. Test for effect of intervention, heterogeneity, trial quality and risk of bias were assessed using the Cochrane Review Manager Software version 5.3.

RESULTS: Five RCTs involving 530 adult patients, with average age of 50± two years old, and average follow-up from six months to three years were included. Combined clinical outcomes of heart failure, cardiac events and all-cause mortality showed an RR of 0.27[95%CI 0.18, 0.40],p<0.00001, in favor of RAS inhibitors. There is same benefit in LVEF preservation with mean difference of 4.37%[95%CI 1.20, 7.55;p=0.007]. Exploratory subgroup analysis showed significant benefit in LVEF preservation with combined RAS inhibitor and beta-blocker, with mean difference of 2.45%[95%CI 1.27, 3.63]. There is overall significant heterogeneity (I2=95%). Excluding one article with high-risk population, after sensitivity analysis, showed same benefit but reduced heterogeneity.

CONCLUSION: Renin angiotensin system (RAS) inhibitors may be used as prophylaxis for cardiotoxicity. As prophylaxis, it reduced the clinical outcome of cardiac events, heart failure, and all-cause mortality among cancer patients needing anthracycline. Combined RAS inhibitor and betablocker limits LVEF reduction.

Human ; Male ; Female ; Cardiotoxicity ; Renin-angiotensin System ; Medline ; Stroke Volume ; Patient Selection ; Follow-up Studies ; Anthracyclines ; Pubmed ; Heart Failure ; Adrenergic Beta-antagonists ; Neoplasms

BACKGROUND: Acute respiratory distress syndrome (ARDS) remains a life-threatening disease. Many patients with ARDS do not recover fully, and progress to terminal lung fibrosis. Angiotensin-converting enzyme (ACE) inhibitor is known to modulate the neurohormonal system to reduce inflammation and to prevent tissue fibrosis. However, the role of ACE inhibitor in the lungs is not well understood. We therefore conducted this study to elucidate the effect of renin-angiotensin system (RAS) blockage on the prognosis of patients with ARDS. METHODS: We analyzed medical records of patients who were admitted to the medical intensive care unit (ICU) at a tertiary care hospital from January 2005 to December 2010. ARDS was determined using the Berlin definition. The primary outcome was the mortality rate of ICU. Survival analysis was performed after adjustment using propensity score matching. RESULTS: A total of 182 patients were included in the study. Thirty-seven patients (20.3%) took ACE inhibitor or angiotensin receptor blocker (ARB) during ICU admission, and 145 (79.7%) did not; both groups showed similar severity scores. In the ICU, mortality was 45.9% in the RAS inhibitor group and 58.6% in the non-RAS inhibitor group (P = 0.166). The RAS inhibitor group required a longer duration of mechanical ventilation (29.5 vs. 19.5, P = 0.013) and longer ICU stay (32.1 vs. 20.2 days, P < 0.001). In survival analysis, the RAS inhibitor group showed better survival rates than the non-RAS group (P < 0.001). CONCLUSIONS: ACE inhibitor or ARB may have beneficial effect on ARDS patients.
Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Berlin ; Case-Control Studies ; Fibrosis ; Humans ; Inflammation ; Intensive Care Units ; Lung ; Medical Records ; Mortality ; Prognosis ; Propensity Score ; Renin-Angiotensin System ; Respiration, Artificial ; Respiratory Distress Syndrome, Adult ; Retrospective Studies ; Survival Rate ; Tertiary Healthcare

OBJECTIVETo examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease.

DATA SOURCESWe searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc.

STUDY SELECTIONThe selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus.

RESULTSCombination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons.

CONCLUSIONSDespite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an evidence-based practice.

Angiotensin Receptor Antagonists ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Animals ; Antihypertensive Agents ; therapeutic use ; Diabetes Mellitus, Type 2 ; complications ; Diabetic Nephropathies ; drug therapy ; Humans ; Renin-Angiotensin System ; drug effects

BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.
Amides/*pharmacology ; Angiotensin II/pharmacology ; Animals ; Disease Models, Animal ; Fibrosis ; Fumarates/*pharmacology ; Kidney/*drug effects/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis, Interstitial/genetics/metabolism/pathology/*prevention & control ; RNA, Messenger/genetics/metabolism ; Renin/*antagonists & inhibitors/metabolism ; Renin-Angiotensin System/*drug effects ; Toll-Like Receptor 2/deficiency/drug effects/genetics/*metabolism ; Ureteral Obstruction/*drug therapy/genetics/metabolism/pathology