Role of Brain Angiotensin-II in Development of Experimental Diabetic Nephropathy in Wistar Rats

Abstract The renin-angiotensin-aldosterone system (RAAS) plays a key role in diabetic nephropathy (DN). Angiotensin-II secreted during the RAAS pathway increases nephropathy. It stimulates oxidative stress which can quench nitric oxide. Reduced nitric oxide level aggravates Ang-II-induced vasoconstriction. Ang-II has also emerged as a central mediator of the glomerular hemodynamic changes that are associated with renal injury. Deletion of ACE2 is also noted due to increased Ang-II level which leads to the development of DN. We hypothesize that nephropathy caused by Ang-II in the periphery may be controlled by brain RAAS. ACE inhibitors and ARBs may show the renoprotective effect when administered through ICV without crossing the blood-brain barrier. DN was observed after 8 weeks of diabetes induction through alloxan. Administration of captopril and valsartan once and in combined therapy for 2 weeks, significantly reduced urine output, blood urea nitrogen, total protein in the urine, serum cholesterol, serum creatinine, serum triglycerides, and kidney/body weight ratio as compared to diabetic control rats. Further, combination therapy significantly increased the body weight and serum nitrate level as compared to diabetic control animals. However, increased ACE2 levels in the brain may reduce the sympathetic outflow and might have decreased the peripheral activity of Ang-II which shows beneficial effects in DN.

Control of sodium and potassium homeostasis by renal distal convoluted tubules

Distal convoluted tubules (DCT), which contain the Na-Cl cotransporter (NCC) inhibited by thiazide diuretics, undergo complex modulation to preserve Na+ and K+ homeostasis. The lysine kinases 1 and 4 (WNK1 and WNK4), identified as hyperactive in the hereditary disease pseudohypoaldosteronism type 2, are responsible for activation of NCC and consequent hypokalemia and hypertension. WNK4, highly expressed in DCT, activates the SPAK/OSR1 kinases, which phosphorylate NCC and other regulatory proteins and transporters in the distal nephron. WNK4 works as a chloride sensor through a Cl- binding site, which acts as an on/off switch at this kinase in response to changes of basolateral membrane electrical potential, the driving force of cellular Cl- efflux. High intracellular Cl- in hyperkalemia decreases NCC phosphorylation and low intracellular Cl- in hypokalemia increases NCC phosphorylation and activity, which makes plasma K+ concentration a central modulator of NCC and of K+ secretion. The WNK4 phosphorylation by cSrc or SGK1, activated by angiotensin II or aldosterone, respectively, is another relevant mechanism of NCC, ENaC, and ROMK modulation in states such as volume reduction, hyperkalemia, and hypokalemia. Loss of NCC function induces upregulation of electroneutral NaCl reabsorption by type B intercalated cells through the combined activity of pendrin and NDCBE, as demonstrated in double knockout mice (KO) animal models, Ncc/pendrin or Ncc/NDCBE. The analysis of ks-Nedd-4-2 KO animal models introduced the modulation of NEDD4-2 by intracellular Mg2+ activity as an important regulator of NCC, explaining the thiazide-induced persistent hypokalemia.

Kidney xenotransplantation: status quo and development trend of physiological research / 器官移植

Organ transplantation is the most effective treatment for all categories of end-stage organ diseases. To resolve the shortage of donors in organ transplantation, widespread attention has been diverted to xenotransplantation. At present, clinicians mainly highlight the problems related to xenotransplantation rejection and viral infection. The physiology of xenotransplantation has been rarely studied. Kidney performs endocrine function by producing erythropoietin (EPO), renin and activating vitamin D. Although these pathways are usually well preserved in allogeneic transplantation, species-specific differences, especially those between pigs and non-human primates, may still affect the physiological function of transplant organs. In this article, the changes of EPO, renin-angiotensin-aldosterone system (RAAS) and active vitamin D3 of pig and human after xenotransplantation were illustrated, aiming to provide reference for subclinical research of xenotransplantation.

Manejo de la Hipertensión en el SARS-CoV2era: conocimiento actual y perspectivas futuras / Management of Hypertension in the SARS-CoV2era: Current Knowledge and Future Perspectives

The new SARS-CoV2 pandemic has ignited research worldwide, regarding its parameters. Hypertension, a comorbidity with high prevalence among patients with COVID-19 infection, is being extensively studied in the setting of the pandemic. Futhermore, RAAS inhibitors, drugs widely used among hypertensive patients, are on the spotlight regarding their safety during the COVID-19 era. In this review, we present current knowledge regarding both these aspects, as well as the new guidelines for the treatment of hypertensive patients during the pandemic

Effect of Zhenwu Decoction on chronic heart failure rats based on RAAS/NF-κB/ inflammatory factor cascade reaction / 中草药

Objective: To investigate the therapeutic effect and potential mechanism of Zhenwu Decoction (ZWD) on chronic heart failure (CHF) rats. Methods: HPLC fingerprint of ZWD was established. All male SD rats were randomly divided into the sham operation group, the model group, the low, medium and high dose ZWD group (2.187 5, 4.375, and 8.75 g/kg) and the captopril group (10 mg/kg). Except for the sham operation group, the rest of rats were all established into the CHF model rats by ligating the left anterior descending branch of the coronary artery, after 8 weeks, all rats were ig administration for 4 weeks. The hemodynamic, viscera index, HE dyeing test were conducted at the end of experiments. Serum angiotensin II (Ang II), aldosterone (ALD), nuclear factor kappa B (NF-κB), amino terminal brain natriuretic peptide (NT-proBNP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) were determinated by ELISA, and myocardial NF-κB protein expression was detected by Western blotting. Results: Higenamine, paeoniflorin, atractylenolide III, 6-gingerol and dehydrotumulosic acid, the five constituents of Zhenwu Decoction, were identified by HPLC chart. Compared with the model group, the administration of the ZWD significantly improved the hemodynamic parameters (P < 0.05), reduced the organ index (P < 0.05) and improved myocardial injury, reduced the serum Ang II, ALD, NF-κB, NT-proBNP, TNF-α and IL-6 levels and the myocardial NF-κB protein expression (P < 0.05). Conclusion: HPLC results provided an evidence for the quality control and pharmacodynamic substance of ZWD. ZWD can ameliorate CHF, which may be related to the inhibition of renin- angiotensin-aldosterone system (RAAS)/NF-κB/inflammatory factor cascade reaction.

Treatment of RAAS inhibitors for hypertensive patients in the coronavirus disease 2019 pandemic from ESH/ISH/AHA statements / 西安交通大学学报(医学版)

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is spreading all over the word. ACE2 is considered as the target receptor to invade humans. Hypertension is one of the most common non-communicable diseases. Many hypertensive patients are treated with RAAS inhibitors,whichare reported toincrease the expression of ACE2. Hence, whether hypertensive patients should continue the therapy of RAAS inhibitors has become the concern around the world. Considering the recent statements from several authoritative organizations, in this article, we make an in-depth discussion on the use of RAAS inhibitors for hypertensive patients.

Angiotensin 1-7: A Second Window of Protection in Hypertensive Patients

The effects of the renin-angiotensin-aldosterone system on the human body are so diverse and our knowledge about them is ever growing. Angiotensin 1-7 has been proven to play protective roles in patients with cardiovascular disorders including but not limited to hypertension. As is the case with Africa, the prevalence of hypertension in Sudan is rising, and its complications could be delayed by pharmacologically manipulating the levels of renin-angiotensin system metabolites. The aim of this review is to compare the advantageous and deleterious effects of Angiotensin 2 in contrast to those of Angiotensin 1-7 and to assert the well-established protective effects of Angiotensin 1-7 (systemically and locally) in hypertensive patients

RAAS antagonist therapy for prevention of atrial fibrillation in hypertension / 中华全科医师杂志

Hypertension is the most common and controlable risk factor of atrial fibrillation (AF).Resin-angiotensin-aldosterone system (RAAS) antagonist therapy may reduce atrial remodeling and hold promise as “upstream” therapy for AF,especially for the patients with left ventricular hypertrophy and left ventricular dysfunction.The RAAS antagonist therapy for prevention of AF in hypertensive patients needs to be further explored in large scale randomized studies.

Effect of Nature and Flavor Subdivision of Ephedrae Herba on Rats Model of Harmful Fluid Retention in Upper Jiao / 中国实验方剂学杂志

Objective: To study the effective substance foundation of Ephedrae Herba and explore its mechanism, in order to further enrich the theory of drug resistance of Ephedrae Herba.Method: In this experiment, a compound model was used to establish rat model of Harmful Fluid Retention in upper Jiao. The Rats were randomly divided into model group, captopril group (4.38 mg·kg-1), Ephedrae Herba decoction group(468 mg·kg-1), polysaccharide group (265.36 mg·kg-1), volatile oil group (2.34 mg·kg-1), alkaloid group(40.71 mg·kg-1) and phenolic acid group (210.60 mg·kg-1), and normal group (10 mL·kg-1). The normal group and the model group were given the same volume of normal saline for four weeks. The 24 h urine volume of rats was collected by metabolic cage method. The changes of heart and lung tissue morphology were observed under light microscope. The heart index, lung index, left ventricular ejection fraction(LVEF), left ventricular short axis shortening rate(LVFS) and pulmonary permeability index, number(LPI), lung dry-wet ratio(W/D), creatine kinase isoenzyme(CK-MB), angiotensin Ⅱ(Ang Ⅱ), aldosterone(ALD), cardiac aquaporin 1(AQP1), lung AQP1, aquaporin-3(AQP3) and kidney AQP1, aquaporin-2(AQP2), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) change were detected.Result: Compared with the normal group, heart and lungs of the model group were significantly damaged. The amount of 24 h urine, LVEF, LVFS of model rats were significantly reduced(Pα were significantly increased(PPα were significantly increased (PPα were significantly reduced (PPConclusion: Alkaloid components "Wen" and "Xin" are the effective substance basis of its action. The mechanism may be related to the inhibition of renin angiotensin aldosterone system (RAAS) and the anti-inflammatory effect.

Effect of xinmailong injection on NGAL, hs-cTnT and RAAS in elderly patients with type 2 cardio-renal syndrome / 实用医学杂志

Objective Observation of the effects of Xinmailong injection on NGAL, hs-cTnT and RAAS in elderly patients with type 2 cardio-renal syndrome (CRS) , and EvaluatIon of the clinical efficacy and safety.Methods A total of 86 elderly patients who were collected from November 2015 to February 2017 were diagnosed as type 2 CRS in our department of geriatrics. According to the random number table method, they were randomly divided into two groups. Control group (43 cases) were treated with conventional medical therapy and xinmailong group (43 cases) were treated with xinmailong injection with a dose of 5 mg/kg twice a day for 15 days. The value of sneutrophil gelatin-associated apolipoprotein (NGAL) , hypersensitive troponin T (hs-cTnT) , brain natriuretic peptide (BNP) , plasma renin activity (PRA) , and angiotensin Ⅱ (Ang Ⅱ) , aldosterone (ALD) , left ventricular ejection fraction (LVEF) , six-minute walking test and other indicators were measured before and after treatment. Results After treatment, the value of NGAL, hs-cTnT, BNP, PRA, AngⅡ and ALD decreased in both groups, the value of LVEF and six-minute walking distance increased compared with those before treatment (P <0.05); The above indicators in the xinmailong group experienced a more significant alteration than in control group in the same period (P < 0.05); no side effect occurred in both two groups during the experiment. Conclusion Xinmailong injection can reduce the levels of NGAL, hs-cTnT and BNP in elderly patients with type 2 cardio-renal syndrome, improve heart and kidney function, and have curative positive effect and good safety. This study underlined the mechanism of Xinmailong injection may be related to the inhibition of RAAS activity.

Comparison of the efficacy of triple blockade, double blockade and single blockade of RAAS in non diabetic chronic kidney disease

Background: Although dual blockade of the renin-angiotensin-aldosterone system with the combination of an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker is generally well established as a treatment for nephropathy, this treatment is not fully effective in some patients.Methods: A prospective observational study was done on 600 chronic kidney disease patients during July 2012 to August 2014 to compare the efficacy of triple blockade, double blockade and single blockade of renin-angiotensin-aldosterone system in non diabetic chronic kidney disease.Results: At the end of the study, 24 hours urinary protein excretion rate of group I and group III were compared by using student t-test and p value (0.0268) was found significant. Similarly, on comparing group II and group III, p value (0.0160) was again found significant.Conclusions: Triple blockade of the renin-angiotensin-aldosterone system was effective for the treatment of proteinuria in patients with non-diabetic nephropathy whose increased urinary protein had not responded sufficiently to a dual blockade.

Comparison between the efficacy of double blockade and single blockade of RAAS in diabetic kidney disease

Background: Diabetic kidney disease is associated with high morbidity and cardiovascular mortality. A number of guidelines and recommendations have been issued over the years recommending the use of renin angiotensin aldosterone system blockade in the management of diabetic kidney disease.Methods: A prospective observational study was done on 750 diabetic chronic kidney disease patients during July 2012 to August 2014 to compare the efficacy of double blockade and single blocked of renin angiotensin aldosterone system in diabetic kidney disease.Results: At the end of 24 months urinary protein excretion rate of group I and group III were compared by using student t-test and p value (0.0268) was found significant. Similarly, on comparing group II and group III, p value (0.0278) was again significant. Mean arterial blood pressure of group I and group III were statistically significant (0.0496) while comparing group II and group III, p value (0.0419) was again significant.Conclusions: The study concludes that the use of double renin angiotensin aldosterone system blockade therapy is more effective than mono-therapy at reducing albuminuria and proteinuiria, and in decreasing blood pressure at the same time not causing significant deterioration in glomerular filtration rate in diabetic kidney disease patients. Novel potassium-lowering therapies are shown to effective compensate the hyperkalemia risk associated with renin angiotensin aldosterone system blockade use in people with diabetic kidney disease, offering promise for more adequate therapy and greater renal and cardiovascular risk protection in the future.

Nephro protection property of double blockade versus single blocked of RAAS in delaying the progression of CKD

Background: Dual renin angiotensin aldosterone system blockade using angiotensin receptor blockers in combination with angiotensin converting enzyme inhibitors is reported to improve proteinuria in non-diabetic patients.Methods: A prospective observational study was done on 810 non-diabetic chronic kidney disease patients during July 2012 to August 2014 to compare the nephro protection property of double blockade and single blocked of renin angiotensin aldosterone system in delaying the progression of chronic kidney disease.Results: At the end of 24 months urinary protein excretion rate of group I and group III were compared by using student t-test and p value (0.0001) was found significant. Similarly, on comparing group II and group III, p value (0.003) was again significant. Mean arterial blood pressure of group I and group III were statistically significant (<0.0496) while comparing group II and group III, p value (0.0419) was again significant.Conclusions: The study concludes that the use of double renin angiotensin aldosterone system blockade therapy is more effective than monotherapy at reducing albuminuria and proteinuiria, and in decreasing blood pressure at the same time not causing significant deterioration in glomerular filtration rate. Newer potassium lowering therapies can effectively and safely correct hyperkalemia and maintain normokalemia in patients receiving background treatment with renin angiotensin aldosterone system blockade. However, the use of new potassium binders for cardiovascular and renal risk reduction with combined renin angiotensin aldosterone system blockade therapy will require phase III trials.

Comparative study on expelling water retention with drastic purgative of crude and vinegar stir-baked Kansui Radix in cancerous ascites rats / 中草药

Objective: To compare the function of expelling water retention with drastic purgative of crude and vinegar stir-baked Kansui Radix in cancerous ascites model rats. Methods: Furosemide was taken as positive control drug, and the cancerous ascites model rats were respectively orally administered with powder of crude and vinegar stir-baked Kansui Radix and their alcohol and water extract for 7 d. The amounts of urine and ascites, the levels of urinary sodium, potassium, chlorideion, and pH value, and the contents of PRA, Ang II, ALD, and ADH in serum were investigated. Results: Compared with model group, the amount of urine of each medication administration group significantly increased (P < 0.05, 0.01), the amount of ascites, the levels of urinary sodium, potassium, chlorideion, and pH value (P < 0.01), and the contents of PRA, Ang II, ALD, and ADH in serum all showed a significant decrease (P < 0.05, 0.01). Among them, the groups which were administered with powder of crude and vinegar stir-baked Kansui Radix were the most significant, and there was no significant difference between the two groups. Conclusion: The powders of crude and vinegar stir-baked Kansui Radix have a remarkable effect on expelling water retention with drastic purgative, and they could improve the symptom of cancerous ascites model rats.

The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement

PURPOSE: In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. MATERIALS AND METHODS: We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed beta-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. RESULTS: There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). CONCLUSION: In MFS patients who underwent ARR, the addition of RAAS blockade to beta-blocker was associated with reduction of aortic dilatation and clinical events.

Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension

Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.

Hypertension in Chronic Glomerulonephritis

Chronic glomerulonephritis (GN), which includes focal segmental glomerulosclerosis and proliferative forms of GN such as IgA nephropathy, increases the risk of hypertension. Hypertension in chronic GN is primarily volume dependent, and this increase in blood volume is not related to the deterioration of renal function. Patients with chronic GN become salt sensitive as renal damage including arteriolosclerosis progresses and the consequent renal ischemia causes the stimulation of the intrarenal renin-angiotensin-aldosterone system(RAAS). Overactivity of the sympathetic nervous system also contributes to hypertension in chronic GN. According to the KDIGO guideline, the available evidence indicates that the target BP should be or =30mg/24 h (i.e., those with both micro-and macroalbuminuria), a lower target of or =30mg/ 24 h. The combination of a RAAS blockade with a calcium channel blocker and a diuretic may be effective in attaining the target BP, and in reducing the amount of urinary protein excretion in patients with chronic GN.

Obesity Associated Hypertension: New Insights into Mechanism

With excess nutrition, the burden of obesity is a growing problem worldwide. The imbalance between energy intake and expenditure leads to variable disorders as all major risk factors for cardiovascular disease. There are many hypothetical mechanisms to explain obesity-associated hypertension. Activation of the RAAS is a key contributing factor in obesity. Particularly, the RAAS in adipose tissue plays a crucial role in adipose tissue dysfunction and obesity-induced inflammation. The phenotypic changes of adipocytes occur into hypertrophy and an inflammatory response in an autocrine and paracrine manner to impair adipocyte function, including insulin signaling pathway. Adipose tissue produce and secretes several molecules such as leptin, resistin, adiponectin, and visfatin, as well as cytokines such as TNF-alpha, IL-6, MCP-1, and IL-1. These adipokines are stimulated via the intracellular signaling pathways that regulate inflammation of adipose tissue. Inflammation and oxidative stress in adipose tissue are important to interact with the microvascular endothelium in the mechanisms of obesity-associated hypertension. Increased microvascular resistance raises blood pressure. Therefore, a regulatory link between microvascular and perivascular adipose tissue inflammation and adipokine synthesis are provided to explain the mechanism of obesity-associated hypertension.

Non-traditional antiarrhythmic medicines for atrial fibrillation / 中国药科大学学报

Atrial fibrillation is the most common arrhythmia in clinical practice.However,the therapeutic effects of traditional antiarrhythmic medicines are far from satisfactory,because of the high rate of arrhythmia recurrence and the potential proarrhythmia effect.Recently,with the further investigation of the mechanisms that initiate and perpetuate atrial fibrillation,and the support of extensive data from clinical trials and animal experiments,thera-peutics based on anti-inflammation,antioxidation,regulation on renin-angiotensin-aldosterone system(RAAS)and gap junction may be new therapeutic targets for the treatment of arrhythmia.In this paper,the potential molecular mechanisms involved in these processes and several clinical trials about some non-traditional antiarrhythmic medi-cines were reviewed,in order to propose a new idea about the development of antiarrhythmic medicines.

The Effects of Aldosterone and Cytokines IL-1beta, TNF-alpha on the Expression of Angiotensin Converting Enzyme Gene in Vascular Smooth Muscle Cells

BACKGROUND: It has been suggested that all components of the renin-angiotensin-aldosterone system (RAAS) are present in the vascular wall and that the vascular RAAS modulates vascular tone and vascular hypertrophy. One of the catalytic step in the RAAS cascade is the local conversion of angiotensin I to angiotensin II (Ang II) by angiotensin converting enzyme (ACE). One of the major sources of ACE in the vasculature is vascular smooth muscle cells (VSMC). Here, we provide insight into the intrinsic mechanisms by which the components of RAAS regulate gene expression of ACE in cultured smooth muscle cells of the rat and we also investigated the effects of cytokines on ACE mRNA. METHODS: RNA was extracted from the primary cultured VSMCs. We analyzed the expression levels of ACE by competitive reverse transcription-PCR using recombinant RNA as an internal standard. RESULTS: 1) ACE mRNA level was increased markedly by aldosterone in a dose- and time-dependent manner, indicating that there exists positive feedback mechanism within RAAS. 2) The induction of ACE mRNA by aldosterone was inhibited by spironolactone. 3) Aldosterone-stimulated expression of ACE was also inhibited by Ang II, which shows that Ang II acts as a negative regulator of the expression of ACE in RAAS cascade. 4) Interleukin-1beta or TNF-alpha did not induce ACE mRNA expression. 5) However, mixture of interleukin-1betaand TNF-alpha(CytoMix) significantly increased the expression of ACE. It was also shown that CytoMix increased aldosterone-stimulated ACE mRNA expression in an additative manner. CONCLUSION: These results indicate that the expression of ACE in smooth muscle cells is modulated by the components of RAAS and cytokines. The intrinsic positive and negative feedback controls of RAAS would play an important role in the pathogenesis of vascular diseases.