angiotensin-i and goralatide

The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.

Topics: Acute Kidney Injury; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Bradykinin; Diabetic Nephropathies; Gene Expression Regulation; Humans; Hypertension; Kidney; Mice; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance

Renin-angiotensin system (RAS) is activated in diabetes. The rise of angiotension II (Ang II) stimulates the cardiac fibroblast proliferation and the alteration of collagen metabolism through AT1 receptor on cell surface, causing the myocardium interstitial and perivascular fibrosis, and the ventricular myocardium rigidity and diastolic function disturbance, leading to the clinical symptoms of diabetic cardiomyopathy (DCM). The main members of RAS including Ang II, Ang-(1-7), Ac-SDKP and ATR play the important role in the development of DCM. This article reviewed the interactions between RAS and endothelin (ET), reactive oxygen species (ROS), transforming growth factor-beta 1 (TGF-beta 1), nuclear factor-kappa b (NF-kappaB), signal transduction system and apoptosis in DCM.

Topics: Angiotensin I; Angiotensin II; Animals; Apoptosis; Diabetic Cardiomyopathies; Humans; NF-kappa B; Oligopeptides; Peptide Fragments; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Signal Transduction; Transforming Growth Factor beta1

Studies analyzing the biochemical and hemodynamic consequences of the insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme gene on angiotensin I and bradykinin metabolism have provided divergent results. Twelve DD and 12 II normotensive subjects were infused for 15 min with angiotensin I (30 ng kg(-1) x min(-1)) and with another angiotensin I converting enzyme substrate not related to the renin-angiotensin system, N-acetyl-Ser-Asp-Lys-Pro (AcSDKP; 1.12 micro g kg(-1) x min(-1)), in the presence and absence of captopril. The infusion of the two peptides was repeated 15 days apart. In both the presence and the absence of captopril we found that DD and II subjects did not significantly differ in terms of endogenous plasma AcSDKP, angiotensin I, or angiotensin II concentrations, and that conversion of exogenous angiotensin I to angiotensin II was not faster in the DD subjects. Exogenously infused AcSDKP was metabolized slightly more rapidly in DD than in II subjects only when angiotensin I converting enzyme was not inhibited. The within-subject variability for angiotensin measurements was high, in contrast to AcSDKP measurements. This variability may account for the divergent results reported to date in the biochemical consequences of the I/D polymorphism of the angiotensin I converting enzyme gene. In conclusion, the I/D polymorphism of the angiotensin I converting enzyme gene has no effect on either endogenous AcSDKP metabolism or on the circulating renin-angiotensin system. It slightly affects the metabolism of exogenously infused AcSDKP and not that of angiotensin I.

Topics: Adolescent; Adult; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cross-Over Studies; Female; Genotype; Homozygote; Humans; Male; Oligopeptides; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Single-Blind Method; Substrate Specificity

This study was designed to compare different proposed methods of assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI) therapy in chronic heart failure.. The use of ACEIs in chronic heart failure gives us a unique opportunity to assess a patient's adherence by measuring whether the expected biochemical effect of an ACEI is present in the patient's bloodstream. In fact, there are several different ways of assessing ACE in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma angiotensin II (AII), or the AII/AI ratio.. Patients with chronic heart failure (n = 39) were randomized to regimens of ACEI nonadherence for one week, ACEI adherence for one week or two versions of partial adherence for one week, after which the above six tests were performed.. All six tests significantly distinguished between full nonadherence for one week and full or partial adherence. Only plasma AcSDKP produced a significantly different result between partial adherence and either full adherence or full nonadherence for one week. In terms of their ability to distinguish full nonadherence from full adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95 and for serum ACE they were 86%, 95% and 0.90.. All six tests distinguished full nonadherence from all other forms of adherence. The rank order of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and plasma AII followed by plasma AI.

Topics: Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Chronic Disease; Diuretics; Drug Therapy, Combination; Echocardiography; Furosemide; Heart Failure; Humans; Lisinopril; Oligopeptides; Peptidyl-Dipeptidase A; Radionuclide Ventriculography; Treatment Outcome; Treatment Refusal

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cell Line; Epithelial-Mesenchymal Transition; Fibrosis; Losartan; Lung; Male; Mice, Inbred C57BL; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Silicosis

The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor.

Topics: Adult; Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Anthracosis; Captopril; Cell Differentiation; Cell Line; Collagen; Disease Models, Animal; Female; Hedgehog Proteins; Humans; Lung; Male; Middle Aged; Myofibroblasts; Oligopeptides; Peptide Fragments; Pulmonary Fibrosis; Rats, Wistar; Renin-Angiotensin System; Signal Transduction; Silicosis

What is the central question of this study? What are the effects of the antifibrotic peptide acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas axis during the occurrence and progression of silicosis? What is the main finding and its importance? Ac-SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2-angiotensin-(1-7)-Mas axis. Angiotensin-(1-7) potentially promotes Ac-SDKP by increasing the level of meprin α, the major synthetase of Ac-SDKP. Thus, the interaction Ac-SDKP and angiotesin-(1-7) in silicosis could provide a new therapeutic strategy.. The central role of angiotensin-converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) can be degraded by ACE. The ACE2-angiotensin-(1-7)-Mas axis is protective and acts to counterbalance the detrimental effects of ACE-angiotensin II (Ang II)-Ang II type 1 receptor and exerts antifibrotic effects. Here, we demonstrate an interaction between Ac-SDKP and Ang-(1-7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac-SDKP increased the level of ACE2-Ang-(1-7)-Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α-smooth muscle actin. Furthermore, exogenous Ang-(1-7) had similar antifibrotic effects and increased the level of meprin α, a major Ac-SDKP synthetase, both in vivo and in vitro. Compared with non-silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang-(1-7) were high in patients with silicosis phase II; and the level of Ac-SDKP was high in the silicosis phase III group. These data imply that Ac-SDKP and Ang-(1-7) have an interactive effect as regulatory peptides of the renin-angiotensin system and exert antifibrotic effects.

Topics: Actins; Angiotensin I; Angiotensin II; Animals; Cell Differentiation; Cells, Cultured; Collagen; Collagen Type I; Fibroblasts; Humans; Male; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Silicosis

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Atrial Natriuretic Factor; Bradykinin; Calcitonin Gene-Related Peptide; Humans; Oligopeptides; Oxytocin; Peptide Fragments; Peptidyl-Dipeptidase A; Prorenin Receptor; Receptor, Bradykinin B1; Receptors, Angiotensin; Receptors, Cell Surface; Renin-Angiotensin System; rho-Associated Kinases

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Bradykinin; Dose-Response Relationship, Drug; Drug Stability; Humans; Male; Mice; Mice, Inbred C57BL; Oligopeptides; Peptidyl-Dipeptidase A; Phosphinic Acids; Substrate Specificity

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Bradykinin; Chymases; Humans; Molecular Mimicry; Oligopeptides; Peptidyl-Dipeptidase A; Protein Structure, Tertiary; Serine Endopeptidases; Substrate Specificity

The phosphinic peptide RXP 407 has recently been identified as the first potent selective inhibitor of the N-active site (domain) of angiotensin-converting enzyme (ACE) in vitro. The aim of this study was to probe the in vivo efficacy of this new ACE inhibitor and to assess its effect on the metabolism of AcSDKP and angiotensin I. In mice infused with increasing doses of RXP 407 (0.1--30 mg/kg/30 min), plasma concentrations of AcSDKP, a physiological substrate of the N-domain, increased significantly and dose dependently toward a plateau 4 to 6 times the basal levels. RXP 407 significantly and dose dependently inhibited ex vivo plasma ACE N-domain activity, whereas it had no inhibitory activity toward the ACE C-domain. RXP 407 (10 mg/kg) did not inhibit the pressor response to an i.v. angiotensin I bolus injection in mice. In contrast, lisinopril infusion (5 and 10 mg/kg/30 min) affected the metabolism of both AcSDKP and angiotensin I. Thus, RXP 407 is the first ACE inhibitor that might be used to control selectively AcSDKP metabolism with no effect on blood pressure regulation.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dose-Response Relationship, Drug; Hydrolysis; Indicators and Reagents; Lisinopril; Male; Mice; Oligopeptides; Peptidyl-Dipeptidase A; Phosphinic Acids; Time Factors

Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase that plays a major role in blood pressure regulation. The demonstration that the hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a natural and specific substrate of the N-active site of ACE suggests that this enzyme may have a new physiological role such as the modulation of hematopoietic stem cells. In vitro studies have shown that ACE inhibitors displayed various potencies in inhibiting the degradation of different natural or synthetic substrates of ACE, among which captopril inhibits AcSDKP hydrolysis more potently than angiotensin I hydrolysis. To look for this selectivity in vivo, we investigated the pharmacodynamic effect of increasing doses of captopril (0.01-10 mg/kg) during the 90 min after i.v. administration to spontaneously hypertensive rats. Plasma and urinary AcSDKP levels were measured. The renin-angiotensin system was evaluated by measurements of ACE activity in plasma samples, using the synthetic substrate Hip-His-Leu, by determinations of plasma renin concentrations and measurements of arterial blood pressure. The results showed that captopril (0.01-0.3 mg/kg) selectively inhibited AcSDKP hydrolysis, with limited effects on the renin-angiotensin system. AcSDKP levels in plasma and urine rose to a plateau 4 times the basal level for doses more than 0.3 mg/kg. All of the parameters reflecting the renin-angiotensin system were significantly affected at doses of 1 and 10 mg/kg. The present study therefore confirms that captopril can be used to protect hematopoietic stem cells during antitumor chemotherapy while having only a limited effect on cardiovascular homeostasis.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Hydrolysis; Injections, Intravenous; Kinetics; Male; Oligopeptides; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Renin; Substrate Specificity; Time Factors

The hemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is degraded by ACE. This study was designed to examine the effect of Ac-SDKP on the contractions to angiotensin I. Experiments were performed on rat aortic rings with endothelium exposed to nitro-L-arginine. Ac-SDKP (10 and 100 microM) significantly augmented angiotensin I ED20 (from 2.0+/-0.4 to 4.2+/-1.0 and 5.0+/-0.9 nM) and ED50 (from 4.3+/-0.7 to 8.6+/-1.0 and 10.7+/-1.3 nM, respectively), but did not alter its maximal response. The contractions to angiotensin II were not affected by Ac-SDKP. No degradation of exogenous Ac-SDKP nor detectable release of endogenous Ac-SDKP were observed in the incubation medium. These results suggest that Ac-SDKP impairs angiotensin I response by inhibiting ACE and subsequent angiotensin II formation.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Drug Interactions; In Vitro Techniques; Male; Oligopeptides; Rats; Rats, Wistar; Vasoconstriction

Angiotensin I-converting enzyme (ACE) is composed of two highly similar domains (referred to here as the N and C domains) that play a central role in blood pressure regulation; ACE inhibitors are widely used in the treatment of hypertension. However, the negative regulator of hematopoiesis, N-acetyl-seryl-aspartyl-lysyl-prolyl (AcSDKP), is a specific substrate of the N domain-active site; thus, in addition to the cardiovascular function of ACE, the enzyme may be involved in hematopoietic stem cell regulation, raising the interest of designing N domain-specific ACE inhibitors. We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. However, of the inhibitors tested, captopril is the only compound able to differentiate to some degree between AcSDKP and angiotensin I inhibition of hydrolysis by wild-type ACE: the K(i) value with AcSDKP as substrate was 16-fold lower than that with angiotensin I as substrate. This raises the possibility of using captopril to enhance plasma AcSDKP levels with the aim of normal hematopoeitic stem cell protection during chemotherapy and a limited effect on the cardiovascular function of ACE.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Captopril; Chlorides; CHO Cells; Cricetinae; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Oligopeptides; Peptidyl-Dipeptidase A; Protein Structure, Tertiary; Substrate Specificity