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 ...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.展开更多
Objective:Chronic kidney disease(CKD)is a progressive disorder characterized by intricate structural and functional alterations in the kidneys,attributable to diverse causative factors.Notably,the therapeutic promise ...Objective:Chronic kidney disease(CKD)is a progressive disorder characterized by intricate structural and functional alterations in the kidneys,attributable to diverse causative factors.Notably,the therapeutic promise of miR-145-5p in addressing renal pathologies has been discerned.This investigation seeks to elucidate the functional role of miR-145-5p in injured kidneys by subjecting human glomerular mesangial cells(HGMCs)to stimulation with Angiotensin II(AngII).Materials and Methods:Cellular viability and the levels of inflammatory mediators were evaluated utilizing Cell Counting Kit-8(CCK-8),quantitative real-time polymerase chain reaction(qRT-PCR),and western blot methodologies,both in the presence of AngII incubation and in scenarios of miR-145p overexpression and downregulation.Furthermore,the cell cycle dynamics were elucidated through Fluorescence-activated Cell Sorting(FACS)analysis.Results:AngII incubation induced an upregulation of miR-145-5p and inflammatory factors including Intercellular Adhesion Molecule 1(ICAM-1),Interleukin 6(IL-6),Interleukin 8(IL-8),and Interleukin 1β(IL-1β).Additionally,it elevated the expression of Cyclin A2,Cyclin D1,and the G2/M cell cycle ratio.Conversely,inhibition of miR-145-5p heightened the levels of inflammatory factors and cell cycle regulators induced by AngII incubation.Reduced expression of miR-145-5p correlated with a downregulation of Interleukin 10(IL-10)expression,concurrently promoting HGMC proliferation under AngII stimulation.Moreover,ectopic miR-145-5p expression demonstrated a reduction in inflammatory factors,cell cyclin regulators,G2/M cell cycle ratio,and overall proliferation.Conclusion:MiR-145-5p exhibited inhibitory effects on the inflammatory response and proliferation induced by Angiotensin II in HGMCs,showcasing its potential as a therapeutic avenue for the treatment of kidney injury.展开更多
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 progress...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.展开更多
Hepatic fibrosis is considered a common response to many chronic hepatic injuries.It is a multifunctional process that involves several cell types,cytokines,chemokines and growth factors leading to a disruption of hom...Hepatic fibrosis is considered a common response to many chronic hepatic injuries.It is a multifunctional process that involves several cell types,cytokines,chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem.In spite of many studies regarding the development of fibrosis,the understanding of the pathogenesis remains obscure.The hepatic tissue remodeling process is highly complex,resulting from the balance between collagen degradation and synthesis.Among the many mediators that take part in this process,the components of the Renin angiotensin system(RAS) have progressively assumed an important role.Angiotensin(Ang)□acts as a profibrotic mediator and Ang-(1-7),the newly recognized RAS component,appears to exert a counter-regulatory role in liver tissue.We briefly review the liver fibrosis process and current aspects of the RAS.This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis,focusing on the putative role of the ACE2-Ang-(1-7)-Mas receptor axis.展开更多
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, the...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.展开更多
Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibi...Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.展开更多
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 angiote...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.展开更多
Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) ...Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.展开更多
The renin-angiotensin system(RAS)has been known for more than a century as a cascade that regulates body fluid balance and blood pressure.AngiotensinⅡ(AngⅡ)has many functions in different tissues;however it is on th...The renin-angiotensin system(RAS)has been known for more than a century as a cascade that regulates body fluid balance and blood pressure.AngiotensinⅡ(AngⅡ)has many functions in different tissues;however it is on the kidney that this peptide exerts its main functions.New enzymes,alternative routes for AngⅡformation or even active AngⅡ-derived peptides have now been described acting on AngⅡAT1or AT2receptors,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 angiotensin converting enzyme(ACE),renin and prorenin,well known by its enzymatic activity,can also activate intracellular signaling pathways,acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor.Moreover,the endocrine RAS,now is also known to have paracrine,autocrine and intracrine action ondifferent tissues,expressing necessary components for local AngⅡformation.This in situ formation,especially in the kidney,increases AngⅡlevels 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 AngⅡeffects,improves the development of new drugs for treating hypertension and cardiovascular diseases.展开更多
文摘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.
基金This work was supported by Nantong Science and Technology Project(MS22022012,MS12021039,MS12018020,MS12018041,JC2020040)Jiangsu Provincial Laboratory Animal Association(DWXH202116)+1 种基金the Doctoral Scientific Research Foundation of Nantong University(135420505015,135422505037)National College Students’Innovation and Entrepreneurship Training Program(202110304036Z).
文摘Objective:Chronic kidney disease(CKD)is a progressive disorder characterized by intricate structural and functional alterations in the kidneys,attributable to diverse causative factors.Notably,the therapeutic promise of miR-145-5p in addressing renal pathologies has been discerned.This investigation seeks to elucidate the functional role of miR-145-5p in injured kidneys by subjecting human glomerular mesangial cells(HGMCs)to stimulation with Angiotensin II(AngII).Materials and Methods:Cellular viability and the levels of inflammatory mediators were evaluated utilizing Cell Counting Kit-8(CCK-8),quantitative real-time polymerase chain reaction(qRT-PCR),and western blot methodologies,both in the presence of AngII incubation and in scenarios of miR-145p overexpression and downregulation.Furthermore,the cell cycle dynamics were elucidated through Fluorescence-activated Cell Sorting(FACS)analysis.Results:AngII incubation induced an upregulation of miR-145-5p and inflammatory factors including Intercellular Adhesion Molecule 1(ICAM-1),Interleukin 6(IL-6),Interleukin 8(IL-8),and Interleukin 1β(IL-1β).Additionally,it elevated the expression of Cyclin A2,Cyclin D1,and the G2/M cell cycle ratio.Conversely,inhibition of miR-145-5p heightened the levels of inflammatory factors and cell cycle regulators induced by AngII incubation.Reduced expression of miR-145-5p correlated with a downregulation of Interleukin 10(IL-10)expression,concurrently promoting HGMC proliferation under AngII stimulation.Moreover,ectopic miR-145-5p expression demonstrated a reduction in inflammatory factors,cell cyclin regulators,G2/M cell cycle ratio,and overall proliferation.Conclusion:MiR-145-5p exhibited inhibitory effects on the inflammatory response and proliferation induced by Angiotensin II in HGMCs,showcasing its potential as a therapeutic avenue for the treatment of kidney injury.
文摘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.
文摘Hepatic fibrosis is considered a common response to many chronic hepatic injuries.It is a multifunctional process that involves several cell types,cytokines,chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem.In spite of many studies regarding the development of fibrosis,the understanding of the pathogenesis remains obscure.The hepatic tissue remodeling process is highly complex,resulting from the balance between collagen degradation and synthesis.Among the many mediators that take part in this process,the components of the Renin angiotensin system(RAS) have progressively assumed an important role.Angiotensin(Ang)□acts as a profibrotic mediator and Ang-(1-7),the newly recognized RAS component,appears to exert a counter-regulatory role in liver tissue.We briefly review the liver fibrosis process and current aspects of the RAS.This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis,focusing on the putative role of the ACE2-Ang-(1-7)-Mas receptor axis.
基金Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Funda o de AmparoàPesquisa do Estado de S o Paulo(FAPESP)and Instituto Nacional de Neurociência Translacional(INNT),Programa de Núcleos de Excelência(PRONEX)(Brazil)
文摘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.
文摘Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.
文摘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.
文摘Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.
基金Supported by Carlos Chagas Filho Rio de Janeiro State Research Foundation(FAPERJ)National Institute of Science and Technology for Structural Biology and BioimagingBrazilian National Research Council(CNPq)
文摘The renin-angiotensin system(RAS)has been known for more than a century as a cascade that regulates body fluid balance and blood pressure.AngiotensinⅡ(AngⅡ)has many functions in different tissues;however it is on the kidney that this peptide exerts its main functions.New enzymes,alternative routes for AngⅡformation or even active AngⅡ-derived peptides have now been described acting on AngⅡAT1or AT2receptors,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 angiotensin converting enzyme(ACE),renin and prorenin,well known by its enzymatic activity,can also activate intracellular signaling pathways,acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor.Moreover,the endocrine RAS,now is also known to have paracrine,autocrine and intracrine action ondifferent tissues,expressing necessary components for local AngⅡformation.This in situ formation,especially in the kidney,increases AngⅡlevels 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 AngⅡeffects,improves the development of new drugs for treating hypertension and cardiovascular diseases.
