Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system

The present letter to the editor is related to the study titled‘Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells’.Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Renin-angiotensin system inhibitors prescriptions in Chinese hospitalized chronic kidney disease patients

BACKGROUND Many guidelines have recommended renin-angiotensin system inhibitors(RASI)as the first-line treatment for patients with chronic kidney disease(CKD).We studied RASI prescription trends from 2010 to 2019,and analyzed the characteristics associated with RASI prescription in Chinese hospitalized CKD patients.AIM To study the prescription of renin angiotensin system inhibitors in hospitalized patients with CKD in China.METHODS It was retrospectively,cross-sectional reviewed RASI prescriptions in hospitalized CKD patients in China from 2010 to 2019.RASI prescribing trends were analyzed from 2010 to 2019,and bivariate and multivariate logistic regression analyses were conducted to identify characteristics associated with RASI prescription.RESULTS A total of 35090 CKD patients were included,with 10043(28.6%)RASI prescriptions.Among these patients,18919(53.9%)met the criteria for RASI treatments based on the 2012 kidney disease:Improving global outcomes guidelines.Of these,7246(38.3%)patients received RASI prescriptions.RASI prescriptions showed an initial rapid increase from 2011 to 2012,reached its peak around 2015 and 2016,and then exhibited a subsequent slight decreasing trend.Both bivariate and multivariate analyses showed that several characteristics,including the male gender,age less than 60-year-old,nephrology department admission,lower CKD stage,history of hypertension or diabetes,proteinuria,glomerulonephritis as the CKD etiology,and non-acute kidney injury were associated with RASI prescriptions.CONCLUSION The frequency of RASI prescriptions showed an initial increase but a slight decreasing trend in more recent years.CKD patients with certain characteristics such as elderly age,advanced disease stage,surgery department admission,or acute kidney injury were less likely to receive RASI prescriptions.In the application of RASI in hospitalized CKD patients is insufficient.The actual clinical practice needs to be improved.The development of related research is helpful to guide the correct choice of clinical treatment strategy.

What have we learned about the kallikrein-kinin and renin-angiotensin systems in neurological disorders?

The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.

Nonalcoholic fatty liver disease and the renin-angiotensin system:Implications for treatment

Nonalcoholic fatty liver disease(NAFLD) is the commonest liver disease in Western countries.Treatment of NAFLD is currently based on lifestyle measures and no effective pharmacologic treatment is available so far.Emerging evidence,mainly from animal studies,suggests that the renin-angiotensin-aldosterone system may be of major importance in the pathogenesis of NAFLD and indicates that angiotensin-converting enzyme inhibitors(ACE-I) and angiotensin receptor blockers(ARBs) as a potentially useful therapeutic approach.However,data from human studies are limited and contradictory.In addition,there are few randomized controlled trials(RCTs) on the effects of ACE-I or ARB in patients with NAFLD and most data are from retrospective studies,pilot prospective studies and post hoc analyses of clinical trials.Accordingly,more and larger RCTs are needed to directly assess the effectiveness of ACE-I and ARBs in NAFLD.

Renin-angiotensin system in the kidney: What is new?

The renin-angiotensin system （RAS） has been known for more than a century as a cascade that regulates body fuid balance and blood pressure. Angiotensin Ⅱ（Ang Ⅱ） has many functions in different tissues; how-ever it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang Ⅱformation or even active Ang Ⅱ-derived peptides have now been described acting on Ang Ⅱ AT1 or AT2 recep-tors, or in receptors which have recently been cloned, such as Mas and AT4. Another interesting observation was that old members of the RAS, such as angioten-sin converting enzyme （ACE）, renin and prorenin, well known by its enzymatic activity, can also activate intra-cellular signaling pathways, acting as an outside-in sig-nal transduction molecule or on the renin/（Pro）renin re-ceptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang Ⅱ formation. This in situ formation, especially in the kidney, increases Ang Ⅱ levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-（1-7）/Mas axis and its antangonistic effect rather than classical deleterious Ang Ⅱ effects, improves the development of new drugs for treating hypertension and cardiovascular diseases.

Renin-angiotensin system blockers-SGLT2 inhibitorsmineralocorticoid receptor antagonists in diabetic kidney disease:A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.

The renin-angiotensin system,mood,and suicide:Are there associations?

Available evidence points to a possible role of the renin-angiotensin system(RAS)in the pathophysiology of mood disorders and suicide.We carried out a critical analysis of literature data regarding this role,with a focus on the proposed association between RAS dysfunction and suicidal behavior.Epidemiological,genetic,and biochemical findings are described,and the pathophysiological hypothesis aiming at explaining the possible relationship between RAS and suicide are discussed.Available findings do support the involvement of the RAS in the neurobiology of suicide,although the exact mechanisms underlying this involvement are still unknown.

Inhibition of the Renin-Angiotensin System and Cardiovascular Mortality in Chronic Hemodialysis Patients

INTRODUCTION: Since the outcomes associated with the use of renin-angiotensin-system inhibitors (RASi) by hemodialysis (HD) patients are not fully known, we investigated their effect on the cardiovascular mortality of chronic HD patients. METHODS: Data from 388 HD patients (237 men and 151 women) who were routinely treated for at least 6 months were analyzed. Treatment with a RASi was the major predictor variable. The main outcome measure was cardiovascular mortality. Cox regression analysis was used to assess for the use of RASi and risk of death. RESULTS: Hypertension was diagnosed in 320 patients (82.5%), and 197 (50.8%) of them were treated with a RASi (treated group) and 191 (49.2%) were not (untreated group). The treated group had a higher prevalence of hypertension, history of congestive heart failure, and presence of ST-T changes. Kaplan-Meier analysis revealed a reduction in risk of cardiovascular death in the treated group during the follow-up period (fig. 2;log-rank: p=0.0379). The multivariate analysis showed that treatment with a RASi was also independently associated with reduced cardiovascular mortality (hazard ratio= 0.184;p=0.0161). CONCLUSIONS: The results of this study suggest a possible association between the treatment with RASi and reduced risk of cardiovascular mortality, independent of their effect of lowering blood pressure.

Ocular renin-angiotensin system with special reference in the anterior part of the eye

The renin-angiotensin system(RAS) regulates blood pressure(BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin Ⅱ, angiotensin converting enzyme 1 and angiotensin Ⅱ type 1 receptor(AngⅡ-ACE1-AT1R) together with angiotensin(1-7), angiotensin converting enzyme 2 and Mas receptor(Ang(1-7)-ACE2-Mas R) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory system accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngⅡ-ACE1-AT1 R and Ang(1-7)-ACE2-Mas R, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure(IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.

Effect of cydosporin on renin-angiotensin system in a rat model of chronic cyclosporine nephropathy

Objective To explore the mechanisms of cyclosporin-induced chronic nephrotoxicity. Methods Radioimmunoassay was used to study the changes of plasma renin activity (PRA) ,plasma angiotensin Ⅱ(Ang Ⅱ),and Aldosterone after rats were given low salt diet and 30 mg?kg-1?d-1of CsAfor 28 days. The protective effects of Radix Salviae Miltiorrhizae or benazepril on these changes were also studied. Results In CsA-treated rats, PRA and Ang Ⅱ levels were significantly elevated as compared with control groups. The elevation was not influenced by injection of Radix Salviae Miltiorrhizae,but could be blocked markedly by benazepril. There was significant difference in Aldosterone levels among the groups except benazepril-treated group showing a decreased Aldosterone level. Conclusion Chronic cyclosporone nephropathy may be related to activation of renin-angiotensin system, especially to the elevation of Ang Ⅱ levels. The different effects of Radix Salviae Miltiorrhizae or benazepril on RAS suggest the different

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

BACKGROUND Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the antiangiogenic and anti-fibrogenic activity of these drugs. AIM To elucidate the role of ARBs and ACE-Is in HCC. METHODS We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma;moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were:(1) prospective or retrospective clinical studies;(2) epidemiological studies;and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.RESULTS Thirty-one studies were selected. Three interventional studies showed that ACEIs had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Treatment of Hypertension, Resistant to Conventional Antihypertensives, in Patients on Maintenance Hemodialysis

Background: Hypertension (HTN) is present in up to 90% of end stage kidney disease (ESRD) patients irrespective of the etiology of their kidney disease. Moreover, it is an important modifiable risk factor for progression to ESRD and its overall cardiovascular morbidity and mortality. Objective: to evaluate, prospectively, the role of Renin-Angiotensin-Aldosterone System blockade (RAAS) in HTN, resistant to 3 conventional antihypertensives, in patients on maintenance hemodialysis (MHD). Patients and methods: A total of 52 such patients were treated with Ramipril and 5 with Losartan after intolerable cough/shortness of breath following Ramipril-use. None of the patients had fluid depletion, renal artery stenosis and primary endocrinopathy. The study group was compared to a matched control group of MHD patients with normal blood pressure following 3 drugs-combination therapies. Results: All patients, with resistant HTN, had significant activation of RAAS system prior to treatment compared to inactive one in the control group. In those with resistant HTN, control of HTN, was established within 2 weeks of therapy and was associated with suppression of the RAAS. Such therapy was associated with minor side effects. Conclusion: Our study has shown that RAAS blockade is safe and effective in controlling such resistant HTN in MHD patients.

Renin-Angiotensin System and Thrombosis

Considerable evidence has accumulated to support the concept that the effects of the renin-agniotensin system can be mediated through two modes: endocrine and paracrine modes.

Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease

Background：Renin-angiotensin system inhibitor and calcium channel blocker （CCB） are widely used in controlling blood pressure （BP） in patients with chronic kidney disease （CKD）.We carried out a meta-analysis to compare the renoprotective effect of the combination of angiotensin-converting enzyme inhibitor （ACEI） or angiotensin receptor blocker （ARB） and CCB （i.e.,ACEI/ARB ＋ CCB） with ACEI/ ARB monotherapy in patients with hypertension and CKD.Methods：Publications were identified from PubMed,Embase,Medline,and Cochrane databases.Only randomized controlled trials （RCTs） of BP lowering treatment for patients with hypertension and CKD were considered.The outcomes of end-stage renal disease （ESRD）,cardiovascular events,BP,urinary protein measures,estimated glomerular filtration rate （GFR）,and adverse events were extracted.Results：Based on seven RCTs with 628 patients,ACEI/ARB ＋ CCB did not show additional benefit for the incidence of ESRD （risk ratio [RR] =0.84;95% confidence interval [CI]：0.52-1.33） and cardiovascular events （RR =0.58;95% CI：0.21-1.63） significantly,compared with ACEI/ARB monotherapy.There were no significant differences in change from baseline to the end points in diastolic BP （weighted mean difference [WMD] =-1.28 mmHg;95% CI：-3.18 to-0.62）,proteinuria （standard mean difference =-0.55;95% CI：-1.41 to-0.30）,GFR （WMD =-0.32 ml/min;95% CI：-1.53 to-0.89）,and occurrence of adverse events （RR =1.05;95% CI：0.72-1.53）.However,ACEI/ARB ＋ CCB showed a greater reduction in systolic BP （WMD =-4.46 mmHg;95% CI：-6.95 to-1.97）,compared with ACEI/ARB monotherapy.Conclusion：ACEI/ARB ＋ CCB had no additional renoprotective benefit beyond than what could be achieved with ACEI/ARB monotherapy.

Genetic polymorphisms of the renin-angiotensin-aldosterone system in Chinese patients with end-stage renal disease secondary to IgA nephropathy

Background Genetic variability in the renin-angiotensin-aldosterone system may modify renal responses to injury and disease progression. The angiotensin I-converting enzyme （ACE） gene insertion/deletion （I/D）, the angiotensinogen （AGT） gene, M235T, the aldosterone synthase （CYP11B2） gene, C-344T, and the angiotensin II type 1 receptor （AT1R） gene, Al166C, have been shown to be associated with IgA nephropathy （IgAN） and its progression. We determined the presence of these polymorphisms in 130 Chinese patients with IgAN, including 47 patients with end-stage renal disease （ESRD） and 120 healthy Chinese subjects, to assess their impact on the susceptibility to disease and the liability of progression to ESRD. Methods Genotyping was performed with DNA isolated from peripheral leucocytes using polymerase chain reaction amplification of the polymorphic sequence, restriction enzyme digestion, and separation and identification of DNA fragments. Clinical data from renal biopsies were collected. Results ACE, AGT, CYP and AT1R genotype distributions were similar in patients with IgAN and in controls. Comparing patients with ESRD （IgAN-ESRD） and those without ESRD （IgAN-non ESRD）, there was a significant increase only in the ACE DD genotype （P 〈0.05） among the four gene polymorphisms. There was significant dominance of the male （P 〈0.05）, more marked hypertension （P 〈0.01）, proteinuria （P 〈0.01） and increased serum creatinine during renal biopsy （P〈0.01） in the IgAN-ESRD group. Conclusion Among the ACE, AGT, ATIR and CYP gene polymorphisms, only the DD genotype may predispose the individual to increased risk of progression to ESRD in the Chinese population.

Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

Objective： To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system （RAAS） among patients with type 2 diabetic kidney disease. Data Sources： We 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 ofmonothempy, 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 Selection： The 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. Results： Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin I I 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. Conclusions： Despite 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.

Proliferation of aortic smooth muscle cells and renin-angiotensin system in SHR rats

目的：探讨ＳＨＲ大鼠主动脉平滑肌细胞（ＡＳＭＣ）异常增殖和肾素血管紧张素系统（ＲＡＳ）的关系．方法：测定血管紧张素Ｉ（Ａｎｇ）、卡托普利（Ｃａｐ）、沙拉新（Ｓａｒ）对培养的ＳＨＲ、ＷＫＹＡＳＭＣ增殖和Ａｎｇ、血管紧张素转化酶（ＡＣＥ）的影响．结果：Ａｎｇ在２％血清培养基中可刺激ＳＨＲＡＳＭＣ增生．ＳＨＲＡＳＭＣ分裂增殖能力比ＷＫＹ强，ＳＨＲＡＳＭＣＲＡＳ处于高功能状态．Ｃａｐ长期（４周）干预显著抑制ＳＨＲＡＳＭＣ异常增殖和Ａｎｇ、ＡＣＥ活性，Ｓａｒ长期干预同样抑制ＳＨＲＡＳＭＣ的增殖和ＡＣＥ活性，但Ａｎｇ水平反而升高．Ｃａｐ短期（２４小时）干预不影响两种大鼠ＡＳＭＣＲＡＳ．结论：Ｃａｐ和Ｓａｒ长期干预通过减少ＳＨＲＡＳＭＣＡｎｇ生成或阻断Ａｎｇ和特异受体结合，抑制其异常增殖．

Postnatal renin-angiotensin system inhibition prevents renal damage from prenatal inflammation in rats

OBJECTIVE:To assess the protective role of benazepril,an angiotensin-converting enzyme inhibitor,in renal damage caused by prenatal inflammation.METHODS:Saline or lipopolysaccharide were administered intraperitoneally to pregnant Sprague-Dawley rats on gestation days 8,10,and 12.After birth,offspring received either tap water or benazepril in water between 7 and 68 weeks.Blood pressure,blood urea nitrogen,creatinine,and 24-h urine volume were measured as indices of renal function.Hematoxylin,eosin,periodic acid-Schiff,and Sirius Red staining were used to evaluate renal damage.RESULTS:Postnatal benazepril treatment ameliorated hypertension and restored normal 24-h urine volume and blood urea nitrogen and serum creatinine levels.Benazepril treatment also reduced glycoprotein accumulation and fibrosis in the glomerulus and in tubular epithelial cells and inhibited nuclear factor-kappa B activation.CONCLUSION:Together with our previous findings that postnatal inhibition of nuclear factor-kappa B activation blocks intra-renal renin-angiotensin system activation,our current data demonstrate that intra-renal activation of the renin-angiotensin system interacts with nuclear factor-kappa B activation to cause renal damage in adulthood following prenatal inflammation.

INCREASED VULNERABILITY OF HYPERTROPHIED MYOCARDIUM TO ISCHEMIA AND REPERFUSION INJURY RELATION TO CARDIAC RENIN-ANGIOTENSIN SYSTEM

Hearts of pressure-overload hypertrophy show an increased activation of intracardiac renin-angiotensin system which may contribute to ischemia and reperfusion injury. The purpose of this study is to evaluate whether the hypertrophied myocardium is more vulnerable to ischemia and reperfusion injury and to find out its relation to the cardiac renin-angiotensin system. Hypertrophied rat hearts induced by abdominal aortic banding for 6 weeks were subjected to 2 hours of hypothermic ischemic arrest followed by 30 minutes of reperfusion, and their cardiac function recovery was compared with that of sham-operated normal control hearts. The cardiac renin activity and angiotensin II content before ischemia and after reperfusion were determined. It was found that both the pre-ischemic renin activity and angiotensin II level were higher in hypertrophied myocardium than those in the control: ischemia and reperfusion injury increased both renin activity and angiotensin II content in the two groups, but the renin activity and angiotensin II level were further elevated after reperfusion in the hypertrophied hearts than those in the control hearts. Meanwhile, the cardiac function recovery after 30 minutes reperfusion in the hypertrophied hearts was poorer than that in the control. Correlation analysis revealed that there was a negative correlation between the cardiac output recovery and the myocardial angiotensin II content (r=-0.841), P<0.001), It is concluded that ischemia and reperfusion injury can activate cardiac renin-angiotensin system in isolated rat heart, which may be responsible for the increased susceptibility of the hypertrophied myocardium to ischemia and reperfusion injury.

Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Aim: We have recently identified a cancer stem cell (CSC) subpopulations within the tumor nests (TNs) and another within the peritumoral stroma (PTS) in liver metastasis from colon adenocarcinoma (LMCA). This study investigated the expression of components of the renin-angiotensin (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), and angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) in LMCA. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 16 LMCA samples for PRR, ACE, ATIIR1 and ATIIR2. Immunofluorescence (IF) IHC staining was performed to investigate co-expression of these components of the RAS with SOX2 or OCT4. NanoString analysis (n = 6) and Western blotting (WB,n = 3) were performed on snap-frozen LMCA samples to confirm mRNA and protein expression, respectively. Results: DAB IHC staining showed the expression of PRR, ACE, ATIIR1 and ATIIR2 within all LMCA samples. NanoString analysis and WB confirmed gene and protein expression of these components of the RAS. IF IHC staining demonstrated expression of PRR, ATIIR1 and ATIIR2 by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS. ACE was expressed on the endothelium of the microvessels within the PTS. ;Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.