Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predic...Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.展开更多
AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl<sub>;</sub>and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND...AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl<sub>;</sub>and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND RESULTS Fifty male Sprague-Dawley rats,weighing（180±20）g,wererandomized into five groups（control group,modelgroup,and three losartan treated groups）,inwhich all rats were given the subcutaneousinjection of 40% CCl<sub>4</sub>（every 3 days for 6 weeks）except for rats of control group.Rats of losartan-treated groups were treated with losartan（20 mg/kg,10 mg/kg,5 mg/kg,daily gavage）,After 6weeks liver tissue and serum samples of all ratswere examined.Serum hyaluronic acid（HA）,procollagen typeⅢ（PCⅢ）were detected byradioimmunoassays,van Giesion collagen stainingwas used to evaluate the extracellular matrix of ratswith liver fibrosis.The expression of AT1receptors,transforming growth factor-beta（TGF-β）,and alpha-smooth muscle actin（a-SMA）inliver tissue were determined byimmunohistochemical techniques.Compared withmodel group,serum ALT and AST of losartan-treated groups were significantly reduced（t=4.20,P【0.01 and t=4.57,P【0.01）.Serum HAand PCⅢalso had significant differences（t=3.53,P【0.01 and t=2.20,P【0.05）.Thedegree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors,TGF-β,and α-SMA in liver tissue.CONCLUSION AT1 receptor antagonist,losartan,could limit the progression of the hepatic fibrosisinduced by CCl<sub>4</sub>.The mechanism may be related tothe decrease in the expression of AT1 receptorsand TGF-β,ameliorating the injury of hepatocytes;activation of local renin-angiotensin system mightrelate to hepatic fibrosis;and during progressionof fibrosis,activated hepatic stellate cells mightexpress AT1 receptors.展开更多
AIM To assess the effect of ACE inhibitor andAng Ⅱ type Ⅰ（AT1）receptor antagonist inpreventing hepatic fibrosis caused by CCl<sub>4</sub>administration in rats;to investigate whether ornot there are ex...AIM To assess the effect of ACE inhibitor andAng Ⅱ type Ⅰ（AT1）receptor antagonist inpreventing hepatic fibrosis caused by CCl<sub>4</sub>administration in rats;to investigate whether ornot there are expression of AT 1 receptors onhepatic stellate cells;and to observe the effectof Ang Ⅱ on proliferation and ECM synthesis ofcultured HSCs.METHODS Studies were conducted in maleSprague-Dawley rats.Except for thehepatofibrotic model group and the controlgroup,in three treated groups,either enalapril（5 mg/kg）,or Iosartan（10 mg/kg）,or enalapril+Iosartan were given to the fibrotic rats bydaily gavage,and saline vehicle was given tomodel and normal control rats.After 6 weeks,liver fibrosis was assessed directly by hepaticmorphometric analysis,which has beenconsidered the gold standard for thequantification of fibrosis.The expressions of AT1 receptors and（α-mooth muscle actin,α-SMA）in liver tissue or isolated hepatic stellate cells（HSCs）were detected by immunohistochemicaltechniques.The effect of Ang Ⅱ on HSCproliferation was determined by MTT method.Effect of Ang Ⅱ on collagen synthesis of HSCswas determined by <sup>3</sup>H-proline incorporation.RESULTS Contrasted to the fibrosis in rats ofthe model group,groups of rats treated with either enalapril or Iosartan,or a combination oftwo drugs showed a limited expansion of theinterstitium（4.23±3.70 vs 11.22±4.79,P【0.05）,but no difference was observedamong three treated groups（5.38±3.43,4.96±2.96,4.23±2.70,P】0.05）.Expression of AT 1receptors was found in fibrotic interstitium offibrotic rats,whereas in normal control rats theywere limited to vasculature only to a very slightdegree.AT 1 receptors were also expressed onactivated HSCs in the culture.At concentrationsfrom 10<sup>-9</sup>to 10<sup>-5</sup>mol/L,Ang Ⅱ stimulated HSCproliferation in culture in a dose-dependentmanner.Increasing Ang Ⅱ concentrationsproduced corresponding increases in <sup>3</sup>H-prolineincorporation.Differences among groups were significant.CONCL展开更多
Objective To review the advances of studies on vitamin D receptor and its role in the pathogenesis of diabetic nephropathy.Data sources A comprehensive search of the PubMed literatures without restriction on the publi...Objective To review the advances of studies on vitamin D receptor and its role in the pathogenesis of diabetic nephropathy.Data sources A comprehensive search of the PubMed literatures without restriction on the publication date was carried out using keywords such as vitamin D receptor and diabetic nephropathy.Study selection Articles related to vitamin D receptor and diabetic nephropathy were selected and carefully analyzed.Results The ligands as well as construction and tissue distribution of vitamin D receptor were summarized.Pathogenesis of diabetic nephropathy was analyzed.The mechanisms underlying the renoprotective role of vitamin D receptor including inhibition of renin-angiotensin system,anti-inflammation,anti-fibrosis and the reduction of proteinuria were reviewed.Mounting evidences from animal and clinical studies have suggested that vitamin D therapy has beneficial effects on the renal systems and the underlying renoprotective mechanisms of the vitamin D receptor-mediated signaling pathways is a hot research topic.Conclusion Our study suggests that vitamin D receptor has a great potential for preventing the progression of diabetic nephropathy via multiple mechanisms.展开更多
Purpose To review evidence-based management of nephropathy in patients with type 2 diabetes.Data sources A literature search (MEDLINE 1966 to 2000) was performed using the key word 'diabetic nephropathy'. Re...Purpose To review evidence-based management of nephropathy in patients with type 2 diabetes.Data sources A literature search (MEDLINE 1966 to 2000) was performed using the key word 'diabetic nephropathy'. Relevant book chapters were also reviewed.Study selection Well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy were selected.Data extraction Data and conclusions from the selected articles that provide solid evidence to the optimal management of diabetic nephropathy were extracted and interpreted in light of our clinical research experience with many thousands of Hong Kong Chinese patients.Results Hypertension, long diabetes duration, poor glycaemic control and central obesity are the most important risk factors. Microalbuminuria is a practical marker to predict overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycaemic control is the mainstay of treatment but effective antihypertensive therapy is also key to delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin Ⅱ receptor antagonists have important renoprotective actions independent of their blood pressure lowering actions. Conclusions Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Monitoring renal function and screening for microalbuminuria will allow the identification of patients with nephropathy at a very early stage for intervention. Tight glycaemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.展开更多
Prehypertension(PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease(CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably...Prehypertension(PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease(CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably from country to country ranging between 21.9% and 52%. Many hypotheses are proposed to explain the underlying pathophysiology of PHTN. The most notable of these implicate the renin-angiotensin system(RAS) and vascular endothelium. However, other processes that involve reactive oxygen species, the inflammatory cytokines, prostglandins and C-reactive protein as well as the autonomic and central nervous systems are also suggested. Drugs affecting RAS have been shown to produce beneficial effects in prehypertensives though such was not unequivocal. On the other hand, drugs such as β-adrenoceptor blocking agents were not shown to be useful. Leading clinical guidelines suggest using dietary and lifestyle modifications as a first line interventional strategy to curb the progress of PHTN; however, other clinically respected views call for using drugs. This review provides an overview of the poten-tial pathophysiological processes associated with PHTN, abridges current intervention strategies and suggests investigating the value of using the "Polypill" in prehypertensive subjects to ascertain its potential in delaying(or preventing) CVD associated with raised blood pressure in the presence of other risk factors.展开更多
Diabetic kidney disease(DKD) is the most common cause of chronic kidney disease, leading to end-stage renal disease and cardiovascular disease. The overall number of patients with DKD will continue to increase in para...Diabetic kidney disease(DKD) is the most common cause of chronic kidney disease, leading to end-stage renal disease and cardiovascular disease. The overall number of patients with DKD will continue to increase in parallel with the increasing global pandemic of type 2 diabetes. Based on landmark clinical trials, DKD has become preventable by controlling conventional factors, including hyperglycemia and hypertension, with multifactorial therapy; however, the remaining risk of DKD progression is still high. In this review, we show the importance of targeting remission/regression of microalbuminuria in type 2 diabetic patients, which may protect against the progression of DKD and cardiovascular events. To achieve remission/regression of microalbuminuria, several steps are important, including the early detection of microalbuminuria with continuousscreening, targeting HbA1c < 7.0% for glucose control, the use of renin angiotensin system inhibitors to control blood pressure, the use of statins or fibrates to control dyslipidemia, and multifactorial treatment. Reducing microalbuminuria is therefore an important therapeutic goal, and the absence of microalbuminuria could be a pivotal biomarker of therapeutic success in diabetic patients. Other therapies, including vitamin D receptor activation, uric acid-lowering drugs, and incretin-related drugs, may also be promising for the prevention of DKD progression.展开更多
AIM： To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system （RAS） components and hemodynamic changes. METHODS： P...AIM： To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system （RAS） components and hemodynamic changes. METHODS： Patients were allocated into 4 groups： mild-to-moderate liver disease （MLD）, advanced liver disease （ALD）, patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity （PRA）, angiotensin （Ang） Ⅰ, Ang Ⅱ, and Ang-（1-7） levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS： PRA and angiotensins were elevated in ALD when compared to MLD and controls （P 〈 0.05）. In contrast, Ang Ⅱ was significantly reduced in MLD. Ang-（1-7）/Ang Ⅱ ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang Ⅱ levels were lower and Ang-（1-7）/Ang Ⅱ ratios were higher in the splanchnic circulation than in the peripheral circulation （0.52 ± 0.08 vs 0.38 ±0.04, P 〈 0.02）, whereas the peripheral circulating Ang Ⅱ/Ang Ⅰ ratio was elevated in comparison to splanchnic levels （0.18 ±0.02 vs 0.13 ±0.02, P 〈 0.04）. Ang-（1-7）/ Ang Ⅱ ratios positively correlated with cardiac output （r = 0.66） and negatively correlated with systemic vascular resistance （r = -0.70）. CONCLUSION： Our findings suggest that the relationship between Ang-（1-7） and Ang Ⅱ may play a role in the hemodynamic changes of human cirrhosis.展开更多
The rostral ventrolateral medulla(RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensinconverting...The rostral ventrolateral medulla(RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensinconverting enzyme 2(ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats(SHRs).Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.展开更多
The coronavirus disease 2019(COVID-19)outbreak is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Angiotensin-converting enzyme 2(ACE2)was rapidly identified as the critical functional receptor f...The coronavirus disease 2019(COVID-19)outbreak is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Angiotensin-converting enzyme 2(ACE2)was rapidly identified as the critical functional receptor for SARS-CoV-2.ACE2 is well-known as a counter-regulator of the renin-angiotensin system(RAS)and plays a key role in the cardiovascular system.Given that ACE2 functions as both a SARS-CoV-2 receptor and a RAS modulator,the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions.Thus,an in-depth summary of the recent progress of ACE2 research and its relationship to the virus is urgently needed to provide possible solution to the dilemma.Here,we summarize the complexity and interplay between the coronavirus,ACE2 and RAS(including anti-RAS drugs).We propose five novel working modes for functional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells,as well as its regulatory mechanism.For the controversy of anti-RAS drugs application,we also give theoretical analysis and discussed for drug application.These will contribute to a deeper understanding of the complex mechanisms of underlying the relationship between the virus and ACE2,and provide guidance for virus intervention strategies.展开更多
There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown.On the other hand,there are ongoing debates about the risk associa... There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown.On the other hand,there are ongoing debates about the risk association of insulin use with cancer.We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer,as well as the current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth.Based on the novel findings from the Hong Kong Diabetes Registry and consistent experimental evidence,we argue that use of insulin to control hyperglycemia is unlikely to contribute to increased cancer risk and that dysregulations in the AMPactivated protein kinase pathway due to reduced insulin action and insulin resistance,the insulin-like growth factor-1(IGF-1)-cholesterol synthesis pathway and renin-angiotensin system,presumably due to reduced insulin secretion and hyperglycemia,may play causal roles in the increased risk of cancer in diabetes.Further exploration into the possible causal relationships between abnormalities of these pathways and the risk of cancer in diabetes is warranted.展开更多
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
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：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...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.展开更多
Background It has been reported that osteopontin has an important role in cardiac fibrosis and remodeling. However, its direct mechanisms remain unclear. The purpose of this study was to investigate the role of angiot...Background It has been reported that osteopontin has an important role in cardiac fibrosis and remodeling. However, its direct mechanisms remain unclear. The purpose of this study was to investigate the role of angiotensin and aldosterone blockades in cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted （MI） rats. Methods Fifty SD rats that survived 24 hours after ligating left anterior descending coronary artery were randomly divided into three groups： MI-saline group （n=15, 5 ml/d）, MI-perindopril group （n=18, perindopril 2 mg·kg^-1·d^-1） and MI-spironolacton （n=-17, spironolacton 20 mg·kg^-1·d^-1）. A sham operation group （n=15） was selected as non-infarcted control. At 6 weeks after treatment, hemodynamic pararmeters and left ventricular function were measured with catheterization, interstitial fibrosis infiltration and cardiomyocyte diameters were evaluated histologically. Myocardium osteopontin protein expression level in the non-infarcted myocardium was detected by Western blotting. Results No osteopontin protein was detected in the myocardium of sham-operation rats. High levels of osteopontin protein expression were detected in the MI-saline rats, but the levels were suppressed in the MI-perindopril and MI-spironolacton rats at 6 weeks following MI （P 〈0.01, respectively）. Compared with the sham operation group, all rats in the MI group showed marked interstitial fibrosis infiltration in the non-infarction area, higher ventricular weight/body weight ratio, significantly increased cardiomyocyte diameter （P 〈0.01, respectively）, and developed significant systolic and diastolic dysfunction as indicated by decreased left ventricular systolic pressure （LVSP） and ±dp/dt, as well as increased left ventricular end-diastolic pressure （LVEDP） （P 〈0.01, respectively）. Angiotensin and aldosterone blockades partly prevented cardiac fibrosis and systolic and diastolic dysfunction （P 〈0.01, respectively）. Conclusion Treatment 展开更多
Background The relationship between cyclosporine-induced chronic nephrotoxicity （CAN） and renin-angiotenein II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin...Background The relationship between cyclosporine-induced chronic nephrotoxicity （CAN） and renin-angiotenein II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin II （ANGII） both in renal tissue and plasma from kidney transplantation patients suffering from CAN. Methods Twenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity （CAN group） and chronic rejection （control group） were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. Renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose （C2）. In vitro, human umbilical vein endothelial cells （HUVEC） and rat mesangial cells （MC） were incubated with different concentrations of CsA （0, 250, 500, 1000 μg/L） for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining. Results Renal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls （P 〈0.05）. The plasma levels of renin, ANGII and C2 in the CAN group were higher than the control group, but no significant difference was found （（0.37±0.12） ng·ml^-1·h^-1 vs （0.20±0.10） ng·ml^-1·h^-1, P=0.076; （122.69±26.73） pg/ml vs （121.88±36.35） pg/ml, P=0.977; （719.04±55.89） ng/ml vs （658.80±90.78） ng/ml, P=0.196, respectively）. In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours （P 〈0.05）. CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner. Conclusions Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The 展开更多
文摘Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.
文摘AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl<sub>;</sub>and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND RESULTS Fifty male Sprague-Dawley rats,weighing（180±20）g,wererandomized into five groups（control group,modelgroup,and three losartan treated groups）,inwhich all rats were given the subcutaneousinjection of 40% CCl<sub>4</sub>（every 3 days for 6 weeks）except for rats of control group.Rats of losartan-treated groups were treated with losartan（20 mg/kg,10 mg/kg,5 mg/kg,daily gavage）,After 6weeks liver tissue and serum samples of all ratswere examined.Serum hyaluronic acid（HA）,procollagen typeⅢ（PCⅢ）were detected byradioimmunoassays,van Giesion collagen stainingwas used to evaluate the extracellular matrix of ratswith liver fibrosis.The expression of AT1receptors,transforming growth factor-beta（TGF-β）,and alpha-smooth muscle actin（a-SMA）inliver tissue were determined byimmunohistochemical techniques.Compared withmodel group,serum ALT and AST of losartan-treated groups were significantly reduced（t=4.20,P【0.01 and t=4.57,P【0.01）.Serum HAand PCⅢalso had significant differences（t=3.53,P【0.01 and t=2.20,P【0.05）.Thedegree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors,TGF-β,and α-SMA in liver tissue.CONCLUSION AT1 receptor antagonist,losartan,could limit the progression of the hepatic fibrosisinduced by CCl<sub>4</sub>.The mechanism may be related tothe decrease in the expression of AT1 receptorsand TGF-β,ameliorating the injury of hepatocytes;activation of local renin-angiotensin system mightrelate to hepatic fibrosis;and during progressionof fibrosis,activated hepatic stellate cells mightexpress AT1 receptors.
文摘AIM To assess the effect of ACE inhibitor andAng Ⅱ type Ⅰ（AT1）receptor antagonist inpreventing hepatic fibrosis caused by CCl<sub>4</sub>administration in rats;to investigate whether ornot there are expression of AT 1 receptors onhepatic stellate cells;and to observe the effectof Ang Ⅱ on proliferation and ECM synthesis ofcultured HSCs.METHODS Studies were conducted in maleSprague-Dawley rats.Except for thehepatofibrotic model group and the controlgroup,in three treated groups,either enalapril（5 mg/kg）,or Iosartan（10 mg/kg）,or enalapril+Iosartan were given to the fibrotic rats bydaily gavage,and saline vehicle was given tomodel and normal control rats.After 6 weeks,liver fibrosis was assessed directly by hepaticmorphometric analysis,which has beenconsidered the gold standard for thequantification of fibrosis.The expressions of AT1 receptors and（α-mooth muscle actin,α-SMA）in liver tissue or isolated hepatic stellate cells（HSCs）were detected by immunohistochemicaltechniques.The effect of Ang Ⅱ on HSCproliferation was determined by MTT method.Effect of Ang Ⅱ on collagen synthesis of HSCswas determined by <sup>3</sup>H-proline incorporation.RESULTS Contrasted to the fibrosis in rats ofthe model group,groups of rats treated with either enalapril or Iosartan,or a combination oftwo drugs showed a limited expansion of theinterstitium（4.23±3.70 vs 11.22±4.79,P【0.05）,but no difference was observedamong three treated groups（5.38±3.43,4.96±2.96,4.23±2.70,P】0.05）.Expression of AT 1receptors was found in fibrotic interstitium offibrotic rats,whereas in normal control rats theywere limited to vasculature only to a very slightdegree.AT 1 receptors were also expressed onactivated HSCs in the culture.At concentrationsfrom 10<sup>-9</sup>to 10<sup>-5</sup>mol/L,Ang Ⅱ stimulated HSCproliferation in culture in a dose-dependentmanner.Increasing Ang Ⅱ concentrationsproduced corresponding increases in <sup>3</sup>H-prolineincorporation.Differences among groups were significant.CONCL
文摘Objective To review the advances of studies on vitamin D receptor and its role in the pathogenesis of diabetic nephropathy.Data sources A comprehensive search of the PubMed literatures without restriction on the publication date was carried out using keywords such as vitamin D receptor and diabetic nephropathy.Study selection Articles related to vitamin D receptor and diabetic nephropathy were selected and carefully analyzed.Results The ligands as well as construction and tissue distribution of vitamin D receptor were summarized.Pathogenesis of diabetic nephropathy was analyzed.The mechanisms underlying the renoprotective role of vitamin D receptor including inhibition of renin-angiotensin system,anti-inflammation,anti-fibrosis and the reduction of proteinuria were reviewed.Mounting evidences from animal and clinical studies have suggested that vitamin D therapy has beneficial effects on the renal systems and the underlying renoprotective mechanisms of the vitamin D receptor-mediated signaling pathways is a hot research topic.Conclusion Our study suggests that vitamin D receptor has a great potential for preventing the progression of diabetic nephropathy via multiple mechanisms.
文摘Purpose To review evidence-based management of nephropathy in patients with type 2 diabetes.Data sources A literature search (MEDLINE 1966 to 2000) was performed using the key word 'diabetic nephropathy'. Relevant book chapters were also reviewed.Study selection Well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy were selected.Data extraction Data and conclusions from the selected articles that provide solid evidence to the optimal management of diabetic nephropathy were extracted and interpreted in light of our clinical research experience with many thousands of Hong Kong Chinese patients.Results Hypertension, long diabetes duration, poor glycaemic control and central obesity are the most important risk factors. Microalbuminuria is a practical marker to predict overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycaemic control is the mainstay of treatment but effective antihypertensive therapy is also key to delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin Ⅱ receptor antagonists have important renoprotective actions independent of their blood pressure lowering actions. Conclusions Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Monitoring renal function and screening for microalbuminuria will allow the identification of patients with nephropathy at a very early stage for intervention. Tight glycaemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.
文摘Prehypertension(PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease(CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably from country to country ranging between 21.9% and 52%. Many hypotheses are proposed to explain the underlying pathophysiology of PHTN. The most notable of these implicate the renin-angiotensin system(RAS) and vascular endothelium. However, other processes that involve reactive oxygen species, the inflammatory cytokines, prostglandins and C-reactive protein as well as the autonomic and central nervous systems are also suggested. Drugs affecting RAS have been shown to produce beneficial effects in prehypertensives though such was not unequivocal. On the other hand, drugs such as β-adrenoceptor blocking agents were not shown to be useful. Leading clinical guidelines suggest using dietary and lifestyle modifications as a first line interventional strategy to curb the progress of PHTN; however, other clinically respected views call for using drugs. This review provides an overview of the poten-tial pathophysiological processes associated with PHTN, abridges current intervention strategies and suggests investigating the value of using the "Polypill" in prehypertensive subjects to ascertain its potential in delaying(or preventing) CVD associated with raised blood pressure in the presence of other risk factors.
基金Supported by A Grant from Novo Nordisk Pharma,to Kitada MA Grant-in-Aid for Scientific Research(C)to Kitada M,No.24591218+4 种基金A Grant for Promoted Research from Kanazawa Medical University to Kitada M,No.S2012-4A Grant-in-Aid for Scientific Research(B)to Koya D,No.25282028A Grant-in-Aid for Challenging Exploratory Research to Koya D,No.25670414A grant for Specially Promoted Research from Kanazawa Medical University to Koya D,No.SR2012-06the 4th Annual Research Award Grant of the Japanese Society of Anti-Aging Medicine,to Koya D
文摘Diabetic kidney disease(DKD) is the most common cause of chronic kidney disease, leading to end-stage renal disease and cardiovascular disease. The overall number of patients with DKD will continue to increase in parallel with the increasing global pandemic of type 2 diabetes. Based on landmark clinical trials, DKD has become preventable by controlling conventional factors, including hyperglycemia and hypertension, with multifactorial therapy; however, the remaining risk of DKD progression is still high. In this review, we show the importance of targeting remission/regression of microalbuminuria in type 2 diabetic patients, which may protect against the progression of DKD and cardiovascular events. To achieve remission/regression of microalbuminuria, several steps are important, including the early detection of microalbuminuria with continuousscreening, targeting HbA1c < 7.0% for glucose control, the use of renin angiotensin system inhibitors to control blood pressure, the use of statins or fibrates to control dyslipidemia, and multifactorial treatment. Reducing microalbuminuria is therefore an important therapeutic goal, and the absence of microalbuminuria could be a pivotal biomarker of therapeutic success in diabetic patients. Other therapies, including vitamin D receptor activation, uric acid-lowering drugs, and incretin-related drugs, may also be promising for the prevention of DKD progression.
基金Supported by Fundacode Amparo à Pesquisa do Estado de Minas Gerais, Conselho Nacional de Desenvolvimento Científico e Tecnológico, FAPEMIG/CNPQ-PRONEX (Grupos de Excelência),Ministério de Ciência e Tecnologia/CNPq/ FAPEMIG-INCT-Nano-Biofar
文摘AIM： To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system （RAS） components and hemodynamic changes. METHODS： Patients were allocated into 4 groups： mild-to-moderate liver disease （MLD）, advanced liver disease （ALD）, patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity （PRA）, angiotensin （Ang） Ⅰ, Ang Ⅱ, and Ang-（1-7） levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS： PRA and angiotensins were elevated in ALD when compared to MLD and controls （P 〈 0.05）. In contrast, Ang Ⅱ was significantly reduced in MLD. Ang-（1-7）/Ang Ⅱ ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang Ⅱ levels were lower and Ang-（1-7）/Ang Ⅱ ratios were higher in the splanchnic circulation than in the peripheral circulation （0.52 ± 0.08 vs 0.38 ±0.04, P 〈 0.02）, whereas the peripheral circulating Ang Ⅱ/Ang Ⅰ ratio was elevated in comparison to splanchnic levels （0.18 ±0.02 vs 0.13 ±0.02, P 〈 0.04）. Ang-（1-7）/ Ang Ⅱ ratios positively correlated with cardiac output （r = 0.66） and negatively correlated with systemic vascular resistance （r = -0.70）. CONCLUSION： Our findings suggest that the relationship between Ang-（1-7） and Ang Ⅱ may play a role in the hemodynamic changes of human cirrhosis.
基金supported by the National Natural Science Foundation of China(81470534,81770419,81630012,and 81570385)the Key Laboratory of Medical Electrophysiology(Southwest Medical University)Ministry of Education of China-No201709(KeyME-2017-09)
文摘The rostral ventrolateral medulla(RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensinconverting enzyme 2(ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats(SHRs).Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.
基金funding support from the National Natural Science Foundation of China(91939301,81820108031,91539123,and 81471893)Beijing Municipal Natural Science Foundation(7172235,China)
文摘The coronavirus disease 2019(COVID-19)outbreak is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Angiotensin-converting enzyme 2(ACE2)was rapidly identified as the critical functional receptor for SARS-CoV-2.ACE2 is well-known as a counter-regulator of the renin-angiotensin system(RAS)and plays a key role in the cardiovascular system.Given that ACE2 functions as both a SARS-CoV-2 receptor and a RAS modulator,the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions.Thus,an in-depth summary of the recent progress of ACE2 research and its relationship to the virus is urgently needed to provide possible solution to the dilemma.Here,we summarize the complexity and interplay between the coronavirus,ACE2 and RAS(including anti-RAS drugs).We propose five novel working modes for functional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells,as well as its regulatory mechanism.For the controversy of anti-RAS drugs application,we also give theoretical analysis and discussed for drug application.These will contribute to a deeper understanding of the complex mechanisms of underlying the relationship between the virus and ACE2,and provide guidance for virus intervention strategies.
基金Supported by The Hong Kong Foundation for Research and Development in Diabetes,Lioa Wun Yuk Diabetes Memorial Fund,established under the auspices of the Chinese University of Hong Kong
文摘 There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown.On the other hand,there are ongoing debates about the risk association of insulin use with cancer.We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer,as well as the current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth.Based on the novel findings from the Hong Kong Diabetes Registry and consistent experimental evidence,we argue that use of insulin to control hyperglycemia is unlikely to contribute to increased cancer risk and that dysregulations in the AMPactivated protein kinase pathway due to reduced insulin action and insulin resistance,the insulin-like growth factor-1(IGF-1)-cholesterol synthesis pathway and renin-angiotensin system,presumably due to reduced insulin secretion and hyperglycemia,may play causal roles in the increased risk of cancer in diabetes.Further exploration into the possible causal relationships between abnormalities of these pathways and the risk of cancer in diabetes is warranted.
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：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.
基金This study was supported by a grant from the Natural Science Foundation of Guangdong Province （No. 4009434）.
文摘Background It has been reported that osteopontin has an important role in cardiac fibrosis and remodeling. However, its direct mechanisms remain unclear. The purpose of this study was to investigate the role of angiotensin and aldosterone blockades in cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted （MI） rats. Methods Fifty SD rats that survived 24 hours after ligating left anterior descending coronary artery were randomly divided into three groups： MI-saline group （n=15, 5 ml/d）, MI-perindopril group （n=18, perindopril 2 mg·kg^-1·d^-1） and MI-spironolacton （n=-17, spironolacton 20 mg·kg^-1·d^-1）. A sham operation group （n=15） was selected as non-infarcted control. At 6 weeks after treatment, hemodynamic pararmeters and left ventricular function were measured with catheterization, interstitial fibrosis infiltration and cardiomyocyte diameters were evaluated histologically. Myocardium osteopontin protein expression level in the non-infarcted myocardium was detected by Western blotting. Results No osteopontin protein was detected in the myocardium of sham-operation rats. High levels of osteopontin protein expression were detected in the MI-saline rats, but the levels were suppressed in the MI-perindopril and MI-spironolacton rats at 6 weeks following MI （P 〈0.01, respectively）. Compared with the sham operation group, all rats in the MI group showed marked interstitial fibrosis infiltration in the non-infarction area, higher ventricular weight/body weight ratio, significantly increased cardiomyocyte diameter （P 〈0.01, respectively）, and developed significant systolic and diastolic dysfunction as indicated by decreased left ventricular systolic pressure （LVSP） and ±dp/dt, as well as increased left ventricular end-diastolic pressure （LVEDP） （P 〈0.01, respectively）. Angiotensin and aldosterone blockades partly prevented cardiac fibrosis and systolic and diastolic dysfunction （P 〈0.01, respectively）. Conclusion Treatment
文摘Background The relationship between cyclosporine-induced chronic nephrotoxicity （CAN） and renin-angiotenein II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin II （ANGII） both in renal tissue and plasma from kidney transplantation patients suffering from CAN. Methods Twenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity （CAN group） and chronic rejection （control group） were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. Renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose （C2）. In vitro, human umbilical vein endothelial cells （HUVEC） and rat mesangial cells （MC） were incubated with different concentrations of CsA （0, 250, 500, 1000 μg/L） for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining. Results Renal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls （P 〈0.05）. The plasma levels of renin, ANGII and C2 in the CAN group were higher than the control group, but no significant difference was found （（0.37±0.12） ng·ml^-1·h^-1 vs （0.20±0.10） ng·ml^-1·h^-1, P=0.076; （122.69±26.73） pg/ml vs （121.88±36.35） pg/ml, P=0.977; （719.04±55.89） ng/ml vs （658.80±90.78） ng/ml, P=0.196, respectively）. In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours （P 〈0.05）. CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner. Conclusions Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The
