Dissertations / Theses on the topic 'Endothelin converting enzyme 1'
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1
Park, Sung-Hae 1971. "Role of endothelin-1 and endothelin converting enzyme-1 in bleomycin-induced pulmonary fibrosis in rats." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=24032.
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Idiopathic pulmonary fibrosis (IPF) belongs to the group of the interstitial lung diseases and is characterized by inflammation, proliferation of fibroblasts and type II pneumocytes, and increased collagen deposition. Inflammatory cells, by releasing mediators and cytokines, participate in the pathogenesis of IPF. Endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide, is one of the mediators that has been shown to be involved in the fibrotic process of IPF in humans. There are, however, no studies examining the role of ET-1 in animal models of IPF. We used the rat model of pulmonary fibrosis, induced by bleomycin, to study the role of ET-1 and endothelin converting enzyme-1 (ECE-1) in IPF using immunohistochemistry (IHC). We also studied by morphometry the effect of bosentan, the mixed ET-A/B receptor antagonist, on the severity of the fibrosis. We found increased ET-1 and ECE-1 immunoreactivities in the lungs of the fibrosis group compared with the control group (P $<$ 0.05), principally in epithelial cells. By morphometry, we found a decrease in the volume fraction (Vv) of air and an increase in the Vv of connective tissue in the fibrosis group compared with control. The fibrosis was significantly reduced by bosentan (P $<$ 0.05). These results are consistent with the notion that ET-1 is an important mediator of bleomycin-induced pulmonary fibrosis.
2
Baluyut, Crystal. "Characterization of human endothelin converting enzyme (ECE-1) promoter diversity in vasular endothelial cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0010/MQ40767.pdf.
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3
Kido, Tsuneo. "Processing of proendothelin-1 at the carboxyl-terminus of big endothelin-1 is essential for proteolysis by endothelin-converting enzyme-1 in vivo." Kyoto University, 1997. http://hdl.handle.net/2433/202209.
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4
Kaburagi, Satoshi. "The role of endothelin-converting enzyme-1 in the development of α1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes." Kyoto University, 2001. http://hdl.handle.net/2433/150597.
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5
Masatsugu, Ken. "Shear stress attenuates endothelin and endothelin-converting enzyme expression through oxidative stress." Kyoto University, 2004. http://hdl.handle.net/2433/147555.
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6
Hasegawa, Hiroshi. "Purification of a novel endothelin-converting enzyme specific for big endothelin-3." Kyoto University, 1998. http://hdl.handle.net/2433/182268.
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7
Harrison, Vanessa Jane. "The characterisation of endothelin-converting enzyme in endothelial cells." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307673.
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8
Ikura, Takeshi. "cDNA cloning and expression of bovine endothelin converting enzyme." Kyoto University, 1997. http://hdl.handle.net/2433/202206.
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9
Govender, Ureshnie. "The characterisation of RAS converting enzyme 1 activity and regulation." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527705.
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10
Hocharoen, Lalintip. "Catalytic Metallopeptide Promoted Inactivation of Enzyme Targets Related to Disease: Angiotensin Converting Enzyme-1 and SortaseA." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354634371.
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11
Jaworski, Jakub. "The role of the deubiquitinating enzyme USP17 in endocytosis and the regulation of Ras converting enzyme 1 activity." Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.602551.
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Ubiquitination and deubiquitination are protein posttranslational modifications that are used in distinct ways to regulate a myriad of cellular activities. Previously, Ubiquitin Specific Protease 17 (USP17) has been shown to be required for cell cycle progression and cell motility. The research presented in this thesis gives further insights into the roles of this deubiquitinating enzyme. The data presented in this thesis reveals that USP17, shown before to hav~ a negative impact on RCE1 activity, in fact regulates the localization and stability of a novel isoform of RCE1. This mammalian specific isoform is required, in addition to the widely recognised RCE1 protein, for proper processing and plasma membrane localization of oncogenic CaaX box GTPase H-Ras. This isoform undergoes K63-type polyubiquitination, which controls its subcellular localization and can be deubiquitinated by USP17, which in turn leads to isoform's destabilization. This represents a novel mechanism of ubiquitination-dependent regulation of RCE1 and explains the critical role of USP17 in cellular processes involving GTPase function such as cell growth and migration. The data presented in this thesis also uncovers a requirement of USP17 for clathrin mediated endocytosis (CM E) of transferrin receptor, an archetypical substrate for this internalization route, and epidermal growth factor receptor (EGFR). In the cells with silenced expression of USP17 a number of core components of the clathrin coated pit, the assembly of which is of key importance in CME, appear to be mislocalized. Further investigation demonstrates that USP17 expression is required for re-localization of phosphatidylinositol-4-phosphate 5-kinase (PIP5K~) to the plasma membrane and localized phosphatidylinositol (4,5)-biphosphate (PIP 2) production, something that plays an indispensable role in the recruitment of the various adaptors and accessory proteins required for CME. Collectively, these data demonstrate that USP17 controls RCE1 activity, through deubiquititation of a novel RCEl isoform, and that its expression is required for CME. These observations may not only be significant to understanding how RCE1 and USP17 function, but may also aid in future drug discovery efforts to target either USP17 or RCE1.
12
Scott, Alasdair James. "The regulation of tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) during acute inflammation." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6041.
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The systemic inflammatory response syndrome (SIRS) describes the immune response to an insult that is inappropriate for a patient’s biological needs. Tumour necrosis factor-α (TNF) is one of the principal pro-inflammatory cytokines that mediates SIRS. TNF-α converting enzyme (TACE) is responsible for the ectodomain cleavage of numerous immunologically relevant substrates including TNF, both TNF receptors and the cellular adhesion molecule L-selectin. The biological significance of TACE lays in its ability to control the availability of these key mediators of the immune response in their membrane-bound and soluble forms. Little is known concerning the regulation of TACE-mediated ectodomain shedding and it contributes to disease pathophysiology. Our objective was to investigate the regulation of TACE catalytic activity and expression during acute inflammation in vitro and in vivo. Our aims were: 1) define the pathways mediating upregulation of TACE activity in primary human monocytes; 2) compare the regulation of TACE catalytic activity and TACE substrate shedding; 3) investigate the acute inflammatory response in elective surgical patients with particular focus on three potential biomarkers of inflammation: TACE expression, HLA-DR expression and circulating monocyte subset populations. We used a fluorimetric assay of TACE activity to demonstrate that lipopolysaccharide (LPS) stimulation of primary human monocytes promotes rapid upregulation of TACE activity, independently of changes in TACE expression. TACE activity upregulation was mediated by reactive oxygen species-induced activation of the p38 MAPK-MK2 pathway. Dithiol oxidation was found to induce L-selectin shedding but to attenuate LPS-induced TACE activity upregulation. Investigation of this paradox revealed that L-selectin shedding may be independent of TACE activity upregulation. Monocyte TACE expression was not modified by low to intermediate risk surgery. In contrast, surgery resulted in downregulation of monocyte HLA-DR expression and differential trafficking of monocyte subsets. These data provide insight into the regulation of TACE during acute inflammation.
13
Scott, Christopher John. "Investigation of expression methodologies for the dissection of the catalytic mechanism of interleukin-1#beta#-converting enzyme." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325991.
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14
Chisi, John Eugenes. "The regulatory role of AcSDKP and angiotensin 1-converting enzyme (ACE) inhibitors on haematopoietic stem and progenitor cell proliferation." Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14971.
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Negative regulatory factors inhibit the proliferation of haematopoietic stem cells thus protecting them from differentiation pressures. One of the negative regulators of stem cell proliferation is the tetrapeptide Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP). This peptide is endogenously produced in vivo and long term bone marrow cultures and is degraded by angiotensin 1-converting enzyme (ACE) both in vivo and in vitro. The aim of these investigations was to study the role of ACE on haematopoietic stem and progenitor cell proliferation. Since the N-domain ACE active has been implicated in AcSDKP degradation, an analysis of two ACE inhibitors (captopril and lisinopril) shown to have differential effects on the N-domain ACE active site was conducted. Both captopril and lisinopril equally reduced ACE activity in plasma in vitro. However, captopril had a lesser effect on reducing serum ACE activity in vitro than lisinopril. Captopril and AcSDKP together reduced the proportion of GM-CFC in S-phase after 7 hours of in vitro incubation. In addition, ACE resistant AcSDKP analogue (AcSDPψKP) when incubated with bone marrow cells in the absence of captopril also reduced the proportion of GM-CFC in S-phase. This finding suggest that the effect of captopril and AcSDKP on GM-CFC proliferation was due to AcSDKP alone. Haematopoietic stem cells were induced into cell cycle by in vivo administration of either 2 Gy-γ-irradiation or the two cytotoxic drugs, cytosine arabinoside (Ara-C) (100 mg/kg i.p.) or 5 flourouracil (5 FU) (150 mg/kg i.v). Bone marrow cells were sampled and incubated in vitro for up to 24 hours. Captopril together with AcSDKP reduced the proportion of high proliferative colony forming cells-1 (HPP-CFC-1) in S-phase following 2 Gy-γ-irradiation. Lisinopril together with AcSDKP had no such effect. In addition, captopril alone in vitro reduced the proportion of HPP-CFC-1 in S-phase induced into cell cycle by cytotoxic drugs. Lisinopril had no such effect. Incubation alone reduced the proportion of HPP-CFC-1 in S-phase in cytotoxic drug treated bone marrow cells. When cultures, which were incubated with captopril, were assayed for AcSDKP levels, captopril induced an increase in AcSDKP levels in both control normal bone marrow cells and cells derived from Ara-C treated mice. However, it did not affect AcSDKP levels in cultures derived from 5 FU and 2 Gy treated mice, AcSDKP together with captopril were shown to inhibit S-phase cell entry of HPP-CFC-1 when they were incubated with bone marrow cells derived from mice treated with either 2 Gy-γ-irradiation or cytotoxic drug insults. Interestingly, captopril was unable to reduce the proportion of SA2 leukaemic cells in S-phase Captopril on its own at therapeutic doses reduced the proportion of HPP-CFC- 1 in S-phase in vivo regardless of the insult used to induce HPP-CFC-1 into cell cycle. Lisinopril slightly reduced the proportion of HPP-CFC-1 in S-phase following Ai-a-C treatment only. Captopril induced an in vivo increase in AcSDKP levels in all the models tested. Captopril also reduced the proportion of HPP-CFC-1 and GM-CFC in S-phase following fractionated doses of Ara-C. Captopril's inhibitory effect on GM- CFC proliferation following fractionated dose of Ara-C was diminished after 7 days while it was sustained with HPP-CFC-1. Long-term bone marrow cultures revealed that captopril and AcSDxj/KP had the same effect on cellularities of both layers and on the proliferation of HPP-CFC and GM-CFC in both layers. From the present investigations, it can be concluded that captopril is a potent inhibitor of HPP-CFC-1 proliferation. This effect may in part be mediated by AcSDKP mechanism.
15
O'Callaghan, David John Patrick. "Investigation into the role of monocyte tumour necrosis factor-alpha converting enzyme as a regulator of the inflammatory response in sepsis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/17943.
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Sepsis consists of both the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS). How these differential response states are regulated is yet to be fully elucidated. Tumour necrosis factor-alpha (TNF) is one of the principal cytokines involved in mediating SIRS. TNF is released from cells by tumour necrosis factor-alpha converting enzyme (TACE), this enzyme is responsible for the ectodomain cleavage of a number of other substrates relevant to inflammation including both TNF receptors and the adhesion molecule L-selectin. How TACE contributes to, and functions in, SIRS and CARS is not yet known. My objective was to investigate TACE activity and associated substrate shedding in monocytes, specifically how the enzyme behaved in the context of in vitro models that I designed to induce states of priming and tolerance. I then obtained in vivo samples from critically ill patients to determine whether there were similarities between the TACE activity profiles found in patient cells, and volunteer cells placed in the in vitro models. My aims were: 1) Determine how TACE activity profiles were altered when sequential inflammatory stimuli were utilised in a two-hit model of sepsis designed to induce states of priming and tolerance and 2) To perform a clinical study to investigate TACE behaviour in the context of critical illness. I successfully refined a method of isolating primary monocytes from healthy volunteers and patients that allowed determination of TACE activity profiles. Furthermore, I demonstrated that the LPS-TACE axis was reset in the context of a two-hit LPS model and in sepsis. I found evidence of differential signalling pathway reprogramming in monocytes taken from patients with infectious and non-infectious SIRS. Finally, I demonstrated that the monocyte TACE response to LPS is dependent on cell contact. These data provide new insights into monocyte inflammatory function during the immune response.
16
Samnegård, Björn. "Renal effects of C-peptide in experimental type-1 diabetes mellitus /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-502-X/.
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17
Dean, Stephanie A. "Regulation of angiotensin converting enzyme and angiotensin II type 1 receptor by 17beta-estradiol in female rats: Implications following experimental myocardial infarction." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26883.
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The present studies tested the hypothesis that 17beta-estradiol (E2) downregulates ACE and AT1R in several tissues important to cardiovascular regulation, including the brain and heart, and that this downregulation attenuates the progression of LV dysfunction following myocardial infarction (MI). In Experiment 1, female Wistar rats were randomized into one of four groups: (1) sham-ovariectomized (OVX); (2) OVX+vehicle (veh); (3) OVX+E2 replacement at physiological levels and (4) OVX+high E2. Five weeks following OVX, ACE and ATIR were increased 15-90% in the heart, several cardiovascular nuclei of the brain, kidney, abdominal aorta, adrenal and lung. These increases were prevented in all cases by E2 replacement at physiological levels and in most cases reversed to decreases by high E2. In Experiment 2, age-matched female Wistar rats underwent 1 of 3 treatments: no surgery (ovary-intact), OVX+veh treatment for two weeks, or OVX+high E2 treatment for two weeks. (Abstract shortened by UMI.)
18
Serfözö, Peter Daniel [Verfasser]. "Angiotensin-Converting Enzyme 2- and Prolyl Carboxypeptidase-Independent Conversion of Angiotensin II to Angiotensin-(1-7) in Circulation and Peripheral Tissues / Peter Daniel Serfözö." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1218076844/34.
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19
Glover, Zoe. "Acer, a homologue of the human angiotensin-1 converting enzyme, modulates the response of sleep, glycogen storage, lifespan, fecundity and stress resistance to diet in Drosophila melanogaster." Thesis, Lancaster University, 2017. http://eprints.lancs.ac.uk/86909/.
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Human angiotensin-1–converting-enzyme (ACE) plays a primary role in the regulation of blood pressure and electrolytes as part of the Renin-Angiotensin System (RAS) in humans. Renin cleaves angiotensinogen to angiotensin I and ACE regulates the vasoconstriction of blood vessels by converting angiotensin-1 to angiotensin-2 (a potent vasoconstrictor) and also by breaking down bradykinin (a potent vasodilator). Renin is regulated by a feedback loop mechanism and is inhibited by higher concentrations of angiotensin-2. A lack of or inhibition of ACE can lead to a reduction in blood pressure (BP) and may reduce the risk of diabetic nephropathy as high BP and high fluid retention can cause swelling in the kidneys. ACE inhibitors are used as treatments for these conditions as well as treating congestive heart failure (Stanley & Samson, 2002). ACE expression has been found in human adipose cells (Jonsson, et al., 1994) and ACE expression in this tissue was reduced when rats were treated with the ACE inhibitor Enalapril (Santos, et al., 2009). Currently ACE’s role in this tissue is unknown and therefore the study of the Drosophila homolog ACER, which is expressed within the fly fat body which is similar in structure to human adipose cells, may highlight a role for ACE in adipose tissue. To investigate the role of ACE-like enzymes in dietary effects on ageing-related and circadian health, function and metabolism we are studying ACER, a homologue of human ACE, in the fruit fly Drosophila melanogaster. Previous studies (Taylor, et al., 1996; Carhan, et al., 2010) have shown that Acer is expressed in the embryonic heart, adult head and adult fat body of the fly. The expression in the fat body is particularly interesting as the fly fat body acts like the human liver and adipose cells where ACE in humans is expressed. Acer’s expression in the head shows a circadian cycle and appears to be regulated by the circadian gene Clock. AcerΔ mutant flies exhibit normal circadian locomotor rhythms but show defects in the regulation of sleep, and the ACE inhibitor, Fosinopril, fed to flies disrupts night time sleep in the same way. This suggests a role for ACER in a circadian phenotypes in Drosophila and therefore a potential circadian role for ACE in humans (Carhan, et al., 2010). The present study has found the effect of the loss of Acer expression in the Acer deletion mutant (AcerΔ) was complex and was often dependent on genetic background and sex. AcerΔ mutants responded normally to dietary restriction (DR) for both sex and background therefore, Acer was not required for the DR response to lifespan. Lipid storage in the AcerΔ mutants was unaffected by the loss of Acer expression but glycogen storage was reduced on high food levels and did not show the normal increase in storage with increasing food compared to controls. Thus, indicating a role for Acer in the modulation of glycogen storage. The genetic backgrounds analysed in this study were the outbred whiteDahomey (wDah) and inbred white1118 (w1118) backgrounds which did show a difference in the effect of the loss of Acer for certain phenotypes. Fecundity in AcerΔ females was lower than in controls in the more fecund wDah background but not in the less fecund w1118 background. Sleep also showed an altered response between the backgrounds and sexes to changing diet in AcerΔ mutants. AcerΔ mutants were starvation and oxidative stress resistant but only in the wDah background and showed sensitivity when compared to controls in the w1118 background. To investigate Acer’s role in the response to nutrition the effect of the loss of Acer on drosophila-insulin-like peptides (dilps) was investigated. Altered transcript levels of dilps in the head and body of the fly in AcerΔ mutants indicated a possible link between Acer and the IIS (insulin/IGF-like signalling) nutrient-sensing pathway. In this study a role for Acer in the modulation of nutrient responsive phenotypes was established.
20
Wang, Yu. "THE ROLE OF THE ACE2/ANG-(1-7)/MASR AXIS IN THE DEVELOPMENT OF OBESITY-HYPERTENSION IN MALE AND FEMALE MICE." UKnowledge, 2016. http://uknowledge.uky.edu/pharmacol_etds/13.
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Obesity is strongly associated with hypertension and cardiovascular diseases. An activated renin-angiotensin system (RAS) has long been suggested as a critical contributor to elevated blood pressure with obesity. Angiotensin II (AngII), the main effector of an activated RAS, can be catabolized by angiotensin-converting enzyme 2 (ACE2) to form angiotensin-(1-7) (Ang-(1-7)), which, acting through the mas receptor (MasR), has been shown to oppose the effects of an activated RAS. Therefore, further understanding of the mechanisms of this counter-regulatory arm, called the ACE2/Ang-(1-7)/MasR axis, may lead to new therapies for obesity-induced hypertension. Previously, we demonstrated that differences in the regulation of ACE2 in a tissue-specific manner contribute to sexual dimorphism of diet-induced obesity-hypertension in mice. Whereas male mice fed a high fat (HF) diet developed hypertension, HF-fed female mice were protected from obesity-hypertension, and this was associated with increased activity of ACE2 in adipose tissue of females. Both upregulation of adipose ACE2 and protection against obesity-hypertension were lost when females were ovariectomized (OVX). We hypothesized that estrogen-mediated increases in adipose ACE2 reduce the AngII/Ang-(1-7) peptide balance and protect females from obesity-hypertension. To test this hypothesis, we first determined if estrogen restores protection of Ovx female mice from obesity-hypertension, and therapeutically protects male mice from obesity-hypertension. We demonstrated that estrogen administration to Ovx HF-fed females activates adipose ACE2, reduces plasma Ang II concentrations, and decreases blood pressure in wildtype, but not of ACE2-deficient obese females. In contrast, estrogen administration to HF-fed male mice had no on the development of obesity-hypertension, regardless of genotype. These results demonstrate that estrogen protects female mice from obesity-hypertension through an ACE2-dependent mechanism. Next we defined the role of MasR deficiency on the development of obesity-hypertension in male and female mice. In HF-fed MasR-deficient female mice, diastolic blood pressure (DBP) was significantly elevated compared to LF-fed controls, suggesting that protection from obesity-hypertension was abolished by MasR deficiency. In contrast, HF-fed male mice with MasR deficiency exhibited reduced blood pressure compared to wildtype controls which was associated with reduced cardiac function. Overall, these studies indicate that the ACE2/Ang-(1-7)/MasR axis plays an important role in sexual dimorphism of obesity-hypertension, and in the regulation of cardiac function. Moreover, these studies suggest that the effects of this counter-regulatory arm of the RAS may be sex-specific.
21
Wang, Peiyu. "Strategy and molecular mechanism study of cold atmospheric plasma applications in oncotherapy, virucide and nanotechnology." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/214016/1/Peiyu_Wang_Thesis.pdf.
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This thesis is the study of cold atmospheric plasma (CAP) applications in cancer, anti-viral treatments, and nano-biotechnology. The optimal treatment strategy, potential molecular mechanism and methods to increase selectivity and efficiency of plasma treatment were investigated for each application. In the near future, CAP or plasma activated medium (PAM) would likely become a widely used, high-efficiency and targeted clinical therapeutic tool.
22
Al, Bacha Jeanne D'Arc. "Nouvelles fonctions de l'enzyme de conversion de l'angiotensine et du récepteur de la (pro)rénine en pathologies cardiovasculaires et neurologiques." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066415.
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De nouveaux composants du système rénine angiotensine (SRA) continuent d'être découverts et leurs fonctions étudiées. Cette thèse présente de nouvelles relations entre enzyme de conversion de l’angiotensine (ECA), thrombose et maladies cardiovasculaires (MCV), d’une part, et d’autre part, un rôle pour le récepteur de la (pro)rénine dans le développement du système nerveux central (SNC). Tout d’abord, nous avons étudié l'association de la double mutation de l’ECA et l’inhibiteur de l’activateur du plasminogène-1 (PAI-1) sur l’incidence d’évènements cardiovasculaires chez les patients Libanais hypertendus et hypercholestérolémiques, par rapport à d'autres gènes cardiovasculaires polymorphes des cytokines pro-inflammatoires dans les cellules mononuclées circulantes. Les résultats ont montré que les patients exprimant une double mutation ECA/PAI-1, respectivement Del/4G, sont à haut risque d’apparition des MCV. Dans une deuxième partie, nous avons étudié la relation entre récepteur de la (pro)rénine dont le gène est appelé Atp6ap2, et la voie de signalisation Wnt/bêta-caténine dans les cellules souches/progénitrices neurales (CSPN). À cette fin, nous avons isolé des CSN à partir d’embryons de souris Atp6ap2-/Y, et étudié leur auto-renouvellement et leur différenciation en neurones, astrocytes et oligodendrocytes in vitro. Nos résultats suggèrent que Atp6ap2 est nécessaire à l’auto-renouvellement des CSN indépendamment de la voie de signalisation Wnt/bêta-caténine chez les mammifères. Enfin, nous avons montré qu’il existait une corrélation entre l’expression ATP6AP2 et le degré de différenciation neuronale des cellules souches mésenchymateuses humaines (CSMh) isolées à partir du tissu adipeuxNew components of the renin angiotensin system (RAS) continue to be discovered and their functions studied. This thesis provides new insights on the role of angiotensin converting enzyme (ACE) in thrombosis and cardiovascular diseases (CVD) and of the (pro)renin receptor in the development of the central nervous system (CNS). First, we studied the role of ACE in CVD by analyzing the impact and the association of a mutation in ACE and in plasminogen activator inhibitor-1 (PAI-1) genes compared to other polymorphic cardiovascular genes of proinflammatory cytokines in peripheral blood mononuclear cells in hypertensive hypercholesterolemic Lebanese patients. We showed that Lebanese patients expressing a double mutation (Del/4G) of ACE and PAI-1, respectively, are at high risk of developing CVD, suggesting that combined ACE/PAI-1 mutations may be considered as a potential marker of CVD onset. In the second part, we studied the relation between the (pro)renin receptor, whose gene is called Atp6ap2, and Wnt/beta-catenin signaling pathway, in neural stem/progenitor cells (NSPC) during development. To this end, we used an in vitro model of neural stem cells (NSC) isolated from Atp6ap2-/Y mice embryos and studied their self-renewal capacity and their differentiation into neurons, astrocytes and oligodendrocytes. Our results suggest that Atp6ap2 is necessary for self-renewal of NSC independently of the Wnt/beta-catenin signaling pathway in mammals. In addition, we showed that the expression of ATP6AP2 in human mesenchymal stem cells (hMSC) isolated from adipose tissue was correlated with their degree of neuronal differentiation
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Raji, Ismaila. "Effect of Tulbaghia violacea on the blood pressure and heart rate in male spontaneously hypertensive wistar rats." Thesis, University of the Western Cape, 2011. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5212_1367481132.
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Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family, Alliaceae, most commonly associated with onions and garlic. In South Africa (SA), this
herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension (HTN) and stomach problems. The aim of this study
was to evaluate the effect of methanol leaf extracts (MLE) of T. violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats
and to find out the mechanism(s) by which it acts. The MLE of T. violacea (5 - 150 mg/kg), angiotensin I (ang I, 3.1 - 100 &mu
g/kg), captopril (10 mg/kg), angiotensin II (ang II, 3.1 - 50
g/kg), losartan (30 mg/kg), phenylephrine (0.01 &ndash
0.16 mg/kg), prazosin (1 mg/kg), dobutamine (0.2 &ndash
10.0 &mu
g/kg), propranolol (0.1 - 12.8 mg/kg), muscarine (0.16 -10 &mu
g/kg),
and atropine (0.02 - 20.48 mg/kg) were administered intravenously into male spontaneously hypertensive rats (SHR) weighing between 300 g and 350 g and aged less than 5
months. The MLE of T. violacea and/or the standard drugs were infused alone, simultaneously, or separately into each animal. The BP and HR were measured via a pressure
transducer connecting the femoral artery and the Powerlab. The vehicle (0.2 mls of a mixture of dimethylsulfoxide and normal saline), T. violacea (60 mg/kg) and captopril (10
mg/kg) were injected intraperitoneally into some SHR for 21 days to investigate the chronic effect of these agents on plasma levels of aldosterone. The mean change, the mean
of the individual percentage changes and the percentage difference (in mean) observed with each intervention was calculated and statistically analyzed using the Student&rsquo
s t test
for significant difference (p <
0.05). The Microsoft Excel software was used for statistical analysis. T. violacea significantly (p <
0.05) reduced the systolic, diastolic, and mean
arterial BP
and HR dose-dependently. In a dose-dependent manner, ang I, ang II, phenylephrine significantly (p <
0.05) increased the BP, while propranolol, muscarine and
atropine reduced the BP. The increases in BP due to dobutamine were not dose-dependent. In a dose dependent manner, phenylephrine and propranolol reduced the HR, while dobutamine increased the HR. The effect of ang I, ang II, muscarine and atropine on HR were not dose-dependent
with both increases as well as decreases observed with ang
I, and II and atropine, while decreases were seen with muscarine. Captopril produced
significant (p <
0.05) reduction in BP which were not associated with any change in HR. The co-infusion of ang I with the MLE produced significant (p <
0.05) reduction in BP, which were not associated with significant changes in HR. The co-infusion of ang II with the
MLE did not produce any significant changes in BP or HR when compared to the infusion of the standard drug alone. The co-infusion of phenylephrine with the MLE did not
produce any significant change in BP or HR when compared to the values obtained with the infusion of the standard drug alone, in both the absence and presence of prazosin.
The co-infusion of dobutamine with T. violacea produced siginificant (p <
0.05) increases in DBP which were associated with significant (p <
0.05) reductions in HR, when
compared to the values obtained with the infusion of the standard drug alone. Theco-infusion of atropine with the MLE did not produce any significant change in BP or HR when
compared to the values obtained with the infusion of atropine alone. However, the infusion of T. violacea, 20 minutes after pre-treating animals with atropine (5.12 mg/kg) lead to
dose dependent significant (p <
0.05) increases in BP, which were associated with dose-dependent increases in HR. The chronic treatment of animals with T. violacea or
captropril produced (a) signicant (p <
0.05) reductions in the plasma levels of aldosterone when compared to the values obtained in the vehicle-treated group, (b) produced
signifiant (p <
0.05) reduction in BP in the captopril treated group when compared to the vehicle-treated, (c) did not produce any signficant change in BP in the T. violacea-treated
group when compared to the vehicle-treated group and (d) did not produce any signifiant change in HR or body weight in any of the groups. The result obtained in this study
suggests that T. violacea reduced BP and HR in the SHR. Secondly, the BP and HR reducing effect of the MLE may involve a) the inhibition of the ACE, b) the inhibition of the &beta
1
adrenoceptors, c) the stimulation of the muscarinic receptors and d) the reduction of the levels of aldosternone in plasma. The results also
suggest that the MLE may not act
through the angiotensin II receptors or the &alpha
1 adrenergic receptors.
24
Cobas, Roberta Arnoldi. "Polimorfismo I/D do gene da enzima conversora de angiotensina e C242T do gene do componente p22phox da NADPH oxidase em pacientes com diabetes tipo 1." Universidade do Estado do Rio de Janeiro, 2009. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=1694.
Full textAbstract:
O sistema renina-angiotensina e o estresse oxidativo têm participação importante na fisiopatologia das complicações crônicas do diabetes. No presente estudo, foram avaliados 103 pacientes com diabetes tipo 1 (DM1) com idade de 28,810,6 anos e duração de doença de 13,18,5 anos e 158 controles não diabéticos quanto à presença dos polimorfismos I/D da ECA e C242T do p22phox, componente essencial para a ativação da NADPH oxidase. Esta análise foi realizada por reação de polimerase em cadeia para ambos os polimorfismos, seguida de restrição enzimática para avaliação do polimorfismo C242T p22phox. Ambas as distribuições genotípicas obedeciam ao princípio do equilíbrio de Hardy-Weinberg. Os pacientes diabéticos foram submetidos a avaliação clínica e laboratorial quanto à presença de fatores associados ao risco de complicações (história de tabagismo e antecedentes familiares de diabetes tipo 2, dose diária de insulina, níveis pressóricos, índice de massa corporal, relação cintura-quadril, excreção urinária de albumina, taxa de filtração glomerular, perfil lipídico, controle glicêmico, níveis de proteína C-reativa) e rastreados quanto à presença de nefropatia diabética, considerada presença de micro ou macroalbuminúria; retinopatia diabética não proliferativa ou proliferativa e hipertensão arterial. Não houve diferença significativa entre a presença dos alelos D e I da ECA ou C e T do p22phox entre diabéticos e controles. Os polimorfismos avaliados não apresentaram associação com a presença de nefropatia, retinopatia ou hipertensão arterial. Pacientes portadores do alelo D apresentaram maiores níveis de pressão arterial diastólica (72,2 12,3 vs 65,4 11,6 mmHg , p=0,047) e proteína C-reativa comparados aos portadores do genótipo II [0,18 (0,04-0,38) vs 0,09 (0,04-0,16) mg/dl, p=0,05] , porém ambas as análises perderam significância estatística após correção para duração do diabetes. A combinação dos polimorfismos não esteve associada à presença de complicações microvasculares ou hipertensão arterial. Concluímos que, na população de diabéticos tipo 1 estudada, a frequência dos polimorfismos I/D da ECA e C242T do p22phox , isoladamente ou em combinação, não apresentou diferença em pacientes com ou sem complicações microvasculares precoces ou hipertensão arterial. Os níveis dos diferentes marcadores de risco cardiovascular também não apresentaram diferença nos pacientes com os polimorfismos acima descritos. Entretanto, estudos prospectivos poderão determinar a possível interação entre estes polimorfismos e a duração do diabetes na expressão clínica das complicações crônicas da doença.The renin-angiotensin system and the oxidative stress play an important role in the pathogenesis of the diabetic complications.In the present study 103 patients with type 1 diabetes (T1DM) aged 28.8 10.6 years and with a disease duration of 13.1 8.5 years and 158 non-diabetic controls were evaluated for the presence of the I / D polymorphism of the angiotensin converting enzyme (ACE) and the C242T polymorphism of the p22phox, an essential component for NADPH oxidase activation. The analysis was performed using polymerase chain reaction for both polymorphisms, followed by enzymatic restriction for C242T p22phox polymorphism. Genotypic distributions of both polymorphisms were in Hardy-Weinberg equilibrium. Diabetic patients underwent clinical and laboratory evaluation for the presence of risk factors associated with complications of diabetes (smoking and family history of type 2 diabetes, daily insulin dose, blood pressure, body mass index, waist hip ratio, urinary albumin excretion, glomerular filtration rate, lipid profile, glycemic control, C-reactive protein levels) and screened for the presence of diabetic nephropathy, considered as the presence of micro or macroalbuminuria, diabetic retinopathy and hypertension. There was no significant difference between the presence of ACE D or I allele and p22phox C or T allele between diabetic patients and controls. The evaluated polymorphisms were not associated with the presence of nephropathy, retinopathy or hypertension. Patients with the D allele showed higher levels of diastolic blood pressure (72.2 12.3 vs 65.4 11.6 mmHg, p = 0.047) and C-reactive protein compared with those carrying the II genotype [0.18 (0.04-0.38) vs 0.09 (0.04-0.16) mg/dl, p = 0.05], but both analysis lost statistical significance after correction for duration of diabetes. The combination of both polymorphisms was not associated with microvascular complications or hypertension. We conclude that in the studied population of type 1 diabetic patients, the frequency of ACE I / D and C242T of p22phox polymorphisms, alone or in combination, was not different in patients with or without early microvascular complications or hypertension. Also, the levels of different markers of cardiovascular risk did not differ for patients with the polymorphisms described above. However, prospective studies may determine the possible interaction between these polymorphisms and duration of diabetes in the clinical expression of chronic complications of diabetes.
25
Wiklund, Per-Gunnar. "Genetic aspects of stroke : association and linkage studies in a northern Swedish population." Doctoral thesis, Umeå : Public Health and Clinical Medicine, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-668.
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Jackson, C. D., K. Barnes, Shervanthi Homer-Vanniasinkam, and A. J. Turner. "Expression and localization of human endothelin-converting enzyme-1 isoforms in symptomatic atherosclerotic disease and saphenous vein." 2006. http://hdl.handle.net/10454/3922.
Full textAbstract:
NoEndothelln-converting enzyme (ECE-1) is a critical enzyme in the production of the potent vasoconstrictor peptide endothelin (ET-1). It has previously been shown that the levels of both ET-1 and ECE-1 are raised in atherosclerosis, but the possible relevance of the isoforms of ECE-1 in these changes has not yet been investigated. The aim of this study was to examine the expression of the ECE-1a and ECE-1c isoforms in human atherosclerotic pathologies. Immunohistochemical analysis was carried out on sections from atherosclerotic and non-atherosclerotic vascular tissue using a combination of ECE-1 isoform-specific antibodies, anti-¿-actin antibodies to identify smooth muscle cells (SMC) and anti-CD68 antibodies to identify macrophages. ECE-1 isoform expression was also examined in cultured SMC and in macrophages isolated from human blood. Results indicated differences in isoform expression in atherosclerotic lesions, with distinct patterns of staining for ECE-1 a and ECE-1 c. ECE-1 c immunoreactivity was seen in macrophages, and also correlated with actin staining. ECE-1a was also localized to macrophages and SMC. Results of this study suggest that these local changes influence the expression patterns of the ECE-1 isoforms within individual cell types. Correlation of these isoform expression patterns with the stage of atherosclerosis could provide novel indicators of disease progression.
27
Xu, Enny-Sonia, and 許恩旎. "The Study of Cytokeratin 17 and Endothelin-Converting Enzyme-1 for Expressions and Prognoses in Head and Neck Cancer." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/kbju63.
Full textAbstract:
博士國立陽明大學
臨床醫學研究所
106
Backgrounds: Head and neck cancer (HNC) affects over 500,000 people worldwide. Head and neck/oral squamous cell carcinoma (HN/OSCC) is the most common histology type of HNC. Cytokeratins (CKs) are mainly expressed in epithelial carcinomas and are valuable for making diagnoses and identifying metastatic status. Changes in the expression of individual CKs in certain carcinoma may be relevant to establishing a prognosis. However, the expression pattern and prognosis status of ECE-1 and the prognostic metastatic and significance of CKs in HNSCC remain vague. In addition, Endothelins (ETs) are 21-amino-acid peptides that have a variety of biologic activities and have been implicated in various pathophysiological conditions, including cancer. Endothelin-1 (ET-1) can promote progression of HNSCC and may be a novel therapeutic target. Endothelin-converting enzyme-1 (ECE-1) primarily converts Big Endothelins (ETs) into active Endothelin-1 (ET-1). However, the expression pattern and prognostication status of ECE-1 in HNSCC are enigmatic. In this study, we investigated the diverse and unique expression patterns of Cytokeratin 13 (CK13) and Cytokeratin 17 (CK17) in epithelial change and assessed the role of CK17 as a predictor for HNSCC metastasis and prognosis; and the role of ECE-1 for expression patterns in tumor differentiation and potential predictor for clinic prognosis in HNC. Methods: CK13, CK17 and ECE-1 expressions were evaluated by using immunohistochemical tissue microarray (TMA) analysis with 126 patients of HNSCC along with their non-neoplastic counterparts. The correlation of CKs and ECE-1 expression to clinicopathologic variables and prognosis was analyzed by using a serial statistical method, during 12-year follow-up. Furthermore, to clarify the characterization of CK17 expression with respect to its ability in predicting metastatic disease, an in-vitro study of cells migration/invasion assays was conducted. Results: CK13 was predominately expressed in noncancerous tissues and was lost in HNSCC. The expression of CK17 was proved that higher in G1 differentiation category than in G2 and G3 differentiation (P = 0.0045). Decreasing expression of CK17 correlated with cancerous cell migration and invasion (P<0.0001) in an in-vitro study. CK17 expression was lower in the N1 and N2 nodal metastases category compared to the N0 stage. Moreover, Kaplan-Meier survival analyses showed that a lower CK17 expression was associated with a poorer survival connotation in HNSCC patients (P < 0.05). On multivariate Cox proportional hazards models analysis, CK17 under-expression proved to be an independent prognostic factor with a hazard ratio (HR) of 1.854 (P = 0.065 < 0.1). In addition, ECE-1 may be over-expressed in HNC carcinoma cells. Higher ECE-1 level was detected more frequently in moderately to poorly differentiated tumors and showed a lower differentiation category compared to the G1 cases (P = 0.015); this finding was further confirmed by an adjusted odds ratio (OR) of 4.071 (P = 0.042). Moreover, Kaplan-Meier survival analyses showed that a higher ECE-1 expression was associated with a poorer survival in HNC patients (P < .0001). On multivariate Cox proportional hazards models analysis, ECE-1 of high-expression proved to be an independent prognostic factor with a hazard ratio (HR) of 3.985 (P < .001). Conclusion: Our findings provide the first evidence that CK17 under-expression might be a potential predictor of nodal metastasis and adverse prognosis, and over-expression ECE-1 in HNC is associated with HNC poor tumor differentiation and clinic outcome.
28
Benoit, Alexandre. "Étude de l'Endothelin-converting enzyme-like 1 (ECEL1), un nouveau membre de la famille de l'endopeptidase neutre-24.11 (EPN)." Thèse, 2004. http://hdl.handle.net/1866/15210.
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Dabouz, Rabah. "La biosynthèse et la localisation subcellulaire de l'endothéline 1 dans les myocytes et les fibroblasts ventriculaires cardiaques adultes." Thèse, 2016. http://hdl.handle.net/1866/18645.
Full textAbstract:
Les récepteurs de type B de l'endothéline (ETB) sont présents sur l'enveloppe nucléaire des cardiomyocytes ventriculaires adultes (MVCAs). Il a été démontré que dans les MVCAs et les cellules endothéliales de rat, l’endocytose de l’endothéline marqué à la rhodamine colocalise avec le Lysotracker, un marqueur des lysosomes, mais n'est pas observée sur l’enveloppe nucléaire. Dans cette étude, nous avons caractérisé la localisation subcellulaire et la régulation de la biosynthèse de l’endothéline 1 dans les MVCAs et les fibroblastes cardiaques adultes de rat. Dans les deux types cellulaires les expériences d’immunocytofluorescence ont révélé une immunoréactivité de l’endothéline 1 correspondant à tous les stades de maturation du peptide, et détectable sur ou à proximité de la membrane nucléaire. L'enzyme de conversion d'endothéline 1(ECE1) est une métalloprotéase qui convertit la ̏ big˝ endothéline 1 en un peptide de 21 acides aminés biologiquement actif. L’immunoréactivité de l’ECE1 a été associée avec les tubules-T et les membranes nucléaires ou périnucléaires dans les MVCAs. Par contre, nous avons observé une immunoréactivité de l’ECE1 à la fois dans le noyau et le cytoplasme, mais pas sur la membrane plasmatique, dans les fibroblastes cardiaques à passage 3. L'ARNm de l’ET-1 a été détecté dans les deux types cellulaires. La régulation de la production de l'endothéline est principalement transcriptionnelle. L’application du facteur de croissance transformant ß1 (TGFß1) a augmenté l’ARNm de l’ET-1 dans les MVCAs et l'angiotensine II a stimulé l'augmentation de l’ARNm de l'ET-1 dans les fibroblastes. Dans les MVCAs, l'augmentation de l'ARNm ET-1 a été associée à une élévation du peptide intracellulaire ET-1 et du calcium nucléaire. Ces données suggèrent que l'endothéline endogène est disponible et serait capable d’activer le récepteur ETB nucléaire dans les MVCAs en réponse à des stimuli extracellulaires.Type B endothelin receptors (ETB) are located in the nuclear envelope of adult ventricular cardiomyocytes (ACVMs). In both ACVMs and endothelial cells, endocytosed rhodamine endothelin colocalized with Lysotracker but was not observed at the nuclear membrane. In this study we have characterized the regulation and subcellular localization of endothelin biosynthesis in ACVMs and adult cardiac fibroblasts. In both cell types immunocytofluorescence experiments revealed endothelin-1 immunoreactivity, comprising all stages of peptide maturation, either on or near the nuclear membrane. Endothelin converting enzyme 1 (ECE1) is a metalloprotease that converts big endothelin to the biologically active 21-amino acid peptide. ECE1 immunoreactivity was associated with the T-tubules and nuclear or perinuclear membranes in ACVMs. In contrast, ECE1 immunoreactivity was observed both in the nucleus and the cytosol, but not at the plasma membrane, in passage 3 cardiac fibroblasts. Endothelin-1 mRNA was detected in both cell types. Regulation of endothelin production is primarily at the level of transcription. Application of TGFβ1 increased ET-1 mRNA in ACVMs whereas angiotensin II was effective in increasing ET-1 mRNA in fibroblasts. In AVCMs, the increase in ET-1 mRNA was associated with an increase of intracellular ET-1 peptide and nuclear calcium. These data suggest that endogenous endothelin is available and may activate nuclear ETB in ACVMs in response to extracellular stimuli.
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"The angiotensin converting enzyme 2 - angiotensin (1-7) axis protects endothelial function against oxidative stress in diabetes." 2013. http://library.cuhk.edu.hk/record=b5884510.
Full textAbstract:
Zhang, Yang.Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 147-169).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
31
"Molecular cloning and characterization of endothelin converting enzyme-2." 2001. http://library.cuhk.edu.hk/record=b5890740.
Full textAbstract:
Ip Lai Fong.Thesis (M.Phil.)--Chinese University of Hong Kong, 2001.
Includes bibliographical references (leaves 81-92).
Abstracts in English and Chinese.
Table of Contents --- p.1
Abbreviations --- p.4
Chapter Chapter 1 --- Introduction and Background --- p.5
Chapter 1.1 --- Endothelin system --- p.5
Chapter 1.1.1 --- Endothelins --- p.5
Chapter 1.1.2 --- Endothelin converting enzyme (ECE) isoforms --- p.12
Chapter 1.1.3 --- Endothelin receptors --- p.24
Chapter 1.2 --- Signal-transduction mechanisms in ET system --- p.27
Chapter 1.3 --- The aim of the present thesis --- p.31
Chapter Chapter 2 --- Materials and Methods --- p.32
Chapter 2.1 --- Primer Design --- p.32
Chapter 2.2 --- Total RNA Isolation --- p.33
Chapter 2.3 --- Reverse transcriptase polymerase chain reaction (RT-PCR) --- p.34
Chapter 2.3.1 --- First Strand cDNA Synthesis --- p.34
Chapter 2.3.2 --- PCR reaction --- p.34
Chapter 2.4 --- Agarose gel electrophoresis --- p.35
Chapter 2.5 --- Ligation of PCR inserts to cloning vector by TA cloning method --- p.35
Chapter 2.6 --- Competent cell preparation --- p.36
Chapter 2.7 --- Transformation and Screening --- p.37
Chapter 2.8 --- Plasmid DNA Extraction --- p.38
Chapter 2.9 --- DNA sequencing --- p.38
Chapter 2.10 --- DIG RNA Labeling --- p.38
Chapter 2.10.1 --- Plasmid Linearization --- p.38
Chapter 2.10.2 --- Transcription --- p.39
Chapter 2.10.3 --- Probe purification --- p.39
Chapter 2.11 --- In situ hybridizaion --- p.40
Chapter 2.11.1 --- Tissue preparation and slide mounting --- p.40
Chapter 2.11.2 --- Non-radioactive in situ hybridization --- p.41
Chapter 2.12 --- Whole Mount non-radioactive in situ hybridization --- p.42
Chapter 2.12.1 --- Dissection and fixation --- p.42
Chapter 2.12.2 --- Hybridization --- p.43
Chapter 2.12.3 --- Antibody incubation --- p.43
Chapter 2.12.4 --- Histochemistry --- p.44
Chapter Chapter 3 --- Results --- p.46
Chapter 3.1 --- The molecular cloning of ECE-2 from rat brain --- p.46
Chapter 3.2 --- Sequence characteristics of rat ECE-2 --- p.52
Chapter 3.3 --- Comparison of rat ECE-2 with bovine and human ECE-2 and with the rat ECE-1 --- p.53
Chapter 3.4 --- Tissue distribution of ECE-2 in rat and localization in C6 glial cells by RT-PCR --- p.60
Chapter 3.5 --- ECE-2 in rat embryos at different gestation stages by RT-PCR --- p.60
Chapter 3.6 --- ECE-2 distribution in C6 glioma cells --- p.63
Chapter 3.7 --- ECE-2 distribution in rat embryo E15.5 --- p.63
Chapter 3.8 --- ECE-2 distribution in rat brain sections --- p.63
Chapter Chapter 4 --- p.74
Discussion --- p.74
References --- p.81
32
吳淑釧. "Improve Morphological Changes and Reduce Vasospasm by Treatment with Selective Endothelin- converting Enzyme Inhibitor Following Experimental Subarachnoid Hemorrhage." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/57750690512237485790.
Full textAbstract:
碩士高雄醫學大學
醫學研究所
90
Endothelin-1（ET-1）is a potent vasoconstrictor that has been implicated in the pathogenesis of cerebral vasospasm after SAH. Endothelin-1（ET-1）is synthesized initially as a large prepropeptide that requires multiple steps of post-translational processing for activation. The final step of this processing involves the proteolytic cleavage of a relatively inactive precursor, big Endothelin-1 （big ET-1）, by the metalloprotease endothelin-converting enzyme （ECE）. Previous studies have demonstrated that endothelin-converting enzyme inhibitor （CGS 26303）could prevent and reverse arterial narrowing in a rabbit model of subarachnoid hemorrhage（SAH）. However, attenuation of vasospastic response was incomplete and required relatively high dose to be effective in reversing vasospasm. Therefore, the first study was designed to examined the effects of a highly selective endothelin-converting enzyme inhibitor, CGS 35066, in the preventing SAH-induced cerebral vasospasm in rabbit model. The ultrastructural changes of mitochondria and endothelial cells of basilar arteries were examined by Transmission Electron Microscopy（TEM）. The reasons why we adapt experiments with rats are comely product just produced from rabbit anti-Endothelin-1 serum and highly selective Endothelin-converting enzyme inhibitor CGS 35066 was difficult to be purified and available. Therefore，the second study planned to another use the Endothelin-converting enzyme inhibitor CGS 26303 in Sprague-Dawley Rat model. In prevention and reversion study，we examined the expression of ET-1 in the basilar arteries of experiment rats with the immunohistochemical stain. Via the use of Transmission Electron Microscopy（TEM）， the ultrastructure was different between the SAH and treatment groups. This gave us an information whether to evaluate the relationship between Endothelial cells change and Endothelin-converting enzyme inhibitor under TEM？ （A）New Zealand white rabbits were subjected to experimental SAH by injecting autogenous blood into the cisterna magna. Endothelin-converting enzyme inhibitor CGS 35066（10 mg/kg）or vehicle was injected intravenously twice daily for two days initially at 1 hour after SAH. Animals were divided into the following seven groups： （1）control（no SAH）；（2）2 days after SAH（no treatment）；（3）7 days after SAH（no treatment）；（4）2 days after SAH＋CGS 35066；（5）7 days after SAH＋CGS 35066；（6）2 days after SAH＋Vehicle；（7）7 days after SAH＋Vehicle. Animals were sacrificed by perfusion fixation 7 days post-SAH. Basilar arteries were removed, sectioned and stained. The ultrastructural changes of mitochondria and endothelial cells were examined by Transmission Electron Microscopy （TEM）. Our results showed that corrugation of endothelial cells and destruction of endothelial cells and mitochondria were obvious in 2 days after SAH and 2 days after SAH＋vehicle animals. In 7days after SAH only animals, no more corrugation of endothelial cells was found, but endothelial cells and mitochondria were severely damaged. However, endothelin-converting enzyme inhibitor CGS 35066 could reserve the intact endothelial cells and mitochondria at 2 days and 7 days after SAH. These finding indicate that intravenous injection of highly selective endothelin-converting enzyme inhibitor can prevent endothelial cells and mitochondrial damage after SAH. Endothelin-converting enzyme inhibitor CGS 35066 can be an alternative approach in the treatment of SAH-induced vasospasm. （B） Reduce level of ET-1 can attenuate vasospastic response. Intravenous infusion of CGS 26303 at doses of 0.24, 0.8, or 2.4 mg/100g/d was initiated 1 hour after SAH in Sprague-Dawley Rat. In prevention study animals were divided into the following six groups： （1）control（no SAH）；（2）SAH only（no treatment）；（3）SAH＋2.4 mg/100 g/d CGS 26303；（4）SAH＋0.8 mg/100 g/d CGS 26303；（5）SAH＋0.24 mg/100 g/d CGS 26303 ；（6）SAH＋Vehicle. In reverse study animals were divided into the following six groups： （1）control（no SAH）； （2） SAH only（no treatment）；（3）SAH＋2.4 mg/100 g/d CGS 26303；（4）SAH＋0.8 mg/100 g/d CGS 26303；（5）SAH＋0.24 mg/100 g/d CGS 26303 ；（6）SAH＋Vehicle. The same procedure was repeated 48 hours after the first experimental SAH. One week later, all animals were killed. Basilar arteries were removed, ET-1 immunohistochemical stain was applied, embedded and sectioned, observed with T.E.M. Dose related attenuation to the positive staining was noticed when compared with SAH only.
33
Chen, Tai-I., and 陳太乙. "Neuroprotective effect of CGS 26303, an endothelin- converting enzyme inhibitor, on the ischemia-reperfusion spinal cord injury in rats." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/66755693595678062984.
Full textAbstract:
碩士高雄醫學大學
醫學研究所碩士班
94
Endothelin-1 (ET-1) has been implicated in many neurological diseases, including subarachnoid hemorrhage and cerebral ischemia. ET-1 is also proved to deteriorate the ischemia-reperfusion injury in many organs yet the spinal cord was not.Our previous studies demonstrated the endothelin-converting enzyme (ECE) inhibitor, CGS26303, possessed beneficial effects for the treatment of SAH and transient middle cerebral artery occlusion. In this study, we investigated the neuroprotective effect of CGS 26303 on locomotor function of rats and mRNA expression of heme-oxygenase-1 (HO-1) using semi-quantitative reverse transcription-polymerase chain reaction after 15 minutes spinal cord ischemia. The results showed rats subjected to spinal cord ischemia with pretreatment by CGS 26303 appeared a significant in preservation in the locomotor function and decreasing the paraplegia rate at Day 1 and 3 as compared with saline-treated group. Furthermore, the rats pretreated with CGS 26303 showed a significant increase in the levels of HO-1 mRNA expression at Day 3 in contrast with the rats pretreated with saline and sham operation group after spinal cord ischemia. These results demonstrated that CGS 26303 may hold the promising neuroprotection in the spinal cord ischemia-reperfusion injury and result from an adaptive mechanism involved by HO-1 overexpression.
34
Bauer, Christian [Verfasser]. "Der Interleukin-1β-converting-enzyme-Inhibitor [Interleukin-1-beta-converting-enzyme-Inhibitor] Pralnacasan reduziert die Dextran-Sulfat-Sodium-induzierte Kolitis und die IL-18-vermittelte Th1-Zell-Aktivierung / vorgelegt von Christian Bauer." 2006. http://d-nb.info/980224101/34.
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Pei-Chun, Hsieh, and 謝佩君. "Association study between hypertension and polymorphisms of angiotensinogen, angiotensin-1 converting enzyme, and lipoprotein lipase genes in Taiwanese." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/45186786515950632452.
Full textAbstract:
碩士國立臺灣大學
農業化學研究所
89
Angiotensinogen (AGT) and angiotensin-I converting enzyme (ACE) play important roles in controlling blood pressure. Nevertheless, studies in various ethnic groups have shown contradictory results on the association between hypertension and genotype of ACE I/D, AGT M235T and T174M polymorphism. Two microsatellite markers, ATA108a05 and LPL, have been linked to young-onset hyperetension in Taiwan. Using 456 Taiwanese subjects that were randomly selected from the general population (the Nutrition and Health Survey in Taiwan, 1993-1996), we examined the association between these genetic polymorphisms and hypertension, and interaction between genetic polymorphisms and dietary factors. Hypertensive subjects had higher levels of body mass index (BMI), plasma triglyceride and uric acid. No association was found between genotypes of any single gene studied and hypertension in this population, but there was an increased risk associated with the presence of both M174 and allele4 of ATA108a05 marker. In people with II genotype, the risk of hypertension decreased with P/S ratio. However, the risk of hypertension increased with P/S ratio in people with DD+DI genotype. The risk of hypertension in people with M235 allele but not in people with T235 significant increased with BMI values. Hypertension risk increased with level of sodium intake in people with M174 allele. However, the risk of hypertension decreased with sodium intake in people with TT genotype. A significant relationship between I/D polymorphism and plasma triglyceride level was incidentally observed in men, but not in women. Further studies are required to confirm the above findings. These results suggest that hypertension is a complex disease which is modulated by gene-environment and gene-gene interactions.
36
Liu, George. "Studies on Angiotensin Converting Enzyme 2, Angiotensin-(1-7), and p47phox-Dependent NADPH Oxidase and their Roles in Diabetic Nephropathy." Thesis, 2012. http://hdl.handle.net/1807/34787.
Full textAbstract:
Diabetic nephropathy is the leading cause of end-stage renal disease, yet the mechanisms responsible for hyperglycemia-induced kidney injury have not been fully elucidated. Activation of the renin-angiotensin system and NADPH oxidase-dependent generation of reactive oxygen species are important mediators of chronic kidney disease. I first studied the effect of ACE2, an important enzyme in the renin-angiotensin system, in diabetic kidney injury in the Akita mouse and related the effect to angiotensin peptide and NADPH oxidase. I then demonstrated the interaction between Angiotensin II, the main substrate, and angiotensin-(1-7), the main product of ACE2, respectively, on cell signaling in mesangial cells to better understand the in vitro effect of ACE2. Finally I studied the effect of deletion of p47phox, a regulatory subunit of the NADPH oxidase, on initiation and progression of diabetic nephropathy in the Akita mouse and mesangial cell.
Administration of human recombinant ACE2 decreased angiotensin II levels, increased angiotensin-(1-7) levels, normalized NADPH oxidase activity in the Akita mice, and ameliorated diabetes-induced kidney injury. In vitro, hrACE2 attenuated both high glucose and ANG II–induced oxidative stress and NADPH oxidase activity in mesangial cells.
Ang-(1–7)-induced ERK1/2 phosphorylation in mesangial cells in a mas receptor-cAMP-PKA-dependent manner. This effect of ang-(1-7) on ERK1/2 phosphorylation is not mediated by AT1R, AT2R, epidermal growth factor or NADPH oxidase. Pre-treatment with Ang-(1-7) attenuated Ang II-induced NADPH oxidase activity and ERK1/2 activation also in a cAMP-PKA-dependent manner.
Deletion of p47phox not only reduced diabetes-induced kidney injury but also reduced hyperglycemia by increasing pancreatic and circulating insulin concentrations. p47phox-/- mice exhibited improved glucose tolerance but modestly decreased insulin sensitivity. Deletion of p47phox attenuated high glucose-induced activation of NADPH oxidase and pro-fibrotic gene expression in mesangial cells. There was a positive correlation between p47phox and collagen Iα1 mRNA levels in renal biopsy samples from control subjects and subjects with diabetic nephropathy.
The data generated in this thesis strongly suggest a protective role of ACE2, via Ang-(1-7), and a deleterious role of p47phox in diabetic nephropathy. Future therapeutic strategies should include enhancing ACE2 activity in the kidney and inhibiting p47phox-dependent activation of NADPH oxidase in both the kidney and the pancreas.
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Wen, Cheng-Hao, and 溫証皓. "Interplay of Angiotensin II and Angiotensin 1-7 in the Modulation of Cardiac Angiotensin-Converting Enzyme II of Human Cardiofibroblasts." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/80516546561355121015.
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碩士國立交通大學
生物科技系所
97
Components of renin–angiotensin system (RAS) are well established targets for pharmacological intervention in a variety of disorders. Many such therapies abrogate the effects of the hypertensive and mitogenic peptide, angiotensin II (Ang II), by antagonising its interaction with its receptor, or by inhibiting its formative enzyme, angiotensin-converting enzyme (ACE). At the turn of the millennium, a novel homologous enzyme, termed ACE2, was identified which increasingly shares the limelight with its better-known homologue. In common with ACE, ACE2 is a type I transmembrane metallopeptidase; however, unlike ACE, ACE2 functions as a carboxypeptidase, cleaving a single C-terminal residue from a distinct range of substrates. ACE2 is a potential therapeutic target for the control of cardiovascular disease owing to its key role in the formation of vasoprotective peptides angiotensin 1-7 (Ang 1-7) from Ang II [cleavage from angiotensin I by angiotensin-converting enzyme (ACE)]. Ang II and Ang 1-7 are both critical regulatory peptides in RAS. Ang II has been documented to play important role in the progression of cardiac remodeling. Elevated Ang II paralleled to cardiac ACE2 upregulation was reported in some pathophysiological conditions, such as myocardial infarction, heart failure and atrial fibrillation. Intracardiac overexpression of ACE2 prevents Ang II induced hypertension and cardiac fibrosis, implicating a direct in vivo cardioprotective role for ACE2, in addition to suggesting possible therapeutic utility. Further evidence for a role of ACE2 in maintaining cardiovascular homeostasis is via Ang II regulation which detected increased ACE2 and Ang 1-7 forming activity in failing human hearts. Hence, we tested the hypothesis that upregulation of ACE2 may provide cardio-protection effects to counteract the elevated Ang II. In the present study, human cardiofibroblast (HCF) cells were used to test the regulatory effects of Ang II and Ang 1-7 on the ACE2 expression at transcriptional and translational level. The results show that Ang II could upregulate ACE2 expression and this action may modulate through the activation of Ang II type I receptor (AT1R). Ang II-mediated ACE2 upregulation could be blocked by the antagonists of downstream targets of AT1R, NADPH oxidase and ERK讣MAPK cascades. To test the Ang II mediated ACE2 promoter activity, our result showed that human cardiac ACE2 promoter activity was significantly upregulation with Ang II stimulation. Additionally, Ang II-induced ACE2 promoter activity could be abolished when the HCF cells pretreated with Valsartan. Furthermore, Ang 1-7 also could up-regulate ACE2 expression in the HCF cells and this upregulation could be inhibited by Mas receptor blocker, A779. Our result shows that the Ang 1-7讣depedent ACE2 upregulation is via Mas receptor signaling pathway and even go through the NADPH oxidase and ERK-MAPK cascades. The confocal fluorescence imaging results provide further validation for Ang II讣 and Ang 1-7讣mediated ACE2 expression and an actual presentation of AT1R and ACE2 localization in HCF cells. Additionally, the image data also show the consistent results with our previous data. In conclusion, our observation implicate that Ang II-induced ACE2 may increase Ang 1-7 formation from Ang II and then the ACE2 expression is further enhanced by the Ang 1-7. According to the results, we proposed a positive feedback-like loop on the cardiac ACE2 regulation for heart to maintain a steady state of RAS. Our results may point out new targets and possibilities for developing novel therapeutic strategies in cardiovascular diseases induced by the dysfunction of RAS.
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Hsu, Wei-Chieh, and 許為捷. "Angiotensin Converting Enzyme Inhibitory Activity and the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) Radical-Scavenging Effect of Various Koji Mold-fermented Black Soybeans." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/03795707061477793224.
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碩士國立臺灣大學
食品科技研究所
99
In this study, black soybeans were fermented with Aspergillus oryzae BCRC 30222, A. sojae BCRC 30103 or Monascus pilosus BCRC 31526 at 30oC and 95% relative humidity for 6 days. The Angiotensin converting enzyme (ACE) inhibitory effect and 2,2-diphenyl -1-picrylhydrazyl (DPPH) radical-scavenging effect exerted by the various fermented black soybeans were then investigated. Besides, the degree of protein hydrolysis, total phenolics, flavonoids and anthocyanin contents of the fermented black soybeans were examined.Results revealed that fermentation, regardless of starters used, significantly enhanced (P<0.05) the ACE inhibitory activity and DPPH radical-scavenging effect of black soybeans and their water extracts. The ACE inhibitory activity and DPPH radical-scavenging effect of the fermented-black soybeans varied with starter organism and fermentation period. The M. pilosus BCRC 31526-fermented black soybeans possessed the highest ACE inhibitory activity and DPPH radical-scavenging effect followed by that fermented by A. oryzae BCRC 30222, and A. sojae BCRC 30103 in descending order. Regardless of starters used, fermentation increased the contents of total phenolics, flavonoids and anthocyanins as well as the degree of protein hydrolysis of black soybean. The enhanced ACE inhibitory activity and DPPH radical-scavenging effect of fermented black soybeans correlated positively with the increases in the degree of protein hydrolysis as well as the contents of total phenolics, flavonoids and anthocyanins.
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Ali, Ismael Mahmoud. "Cardiovascular and sensory abnormalities in a rat model of insulin resistance : beneficial effect of an antioxidant and an angiotensin-1 converting enzyme inhibitor." Thèse, 2007. http://hdl.handle.net/1866/8204.
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Heller, Samuel. "Aldosteron syntáza u arteriální hypertenze a možný vliv polymorfismu jejího genu na hypertrofii levé komory srdeční." Doctoral thesis, 2013. http://www.nusl.cz/ntk/nusl-326710.
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Part I. The aldosterone synthase gene (CYP11B2) polymorphism T-344C in blood pressure and left ventricular hypertrophy. BACKGROUND: Aldosterone is a key cardovascular hormone, it significantly influences volume, pressure and electrolyte balance. Aldosterone plays an important role in development of left ventricular (LV) hypertrophy and myocardial fibrosis. The aldosterone synthase gene (CYP11B2) is an important candidate gene region in essential hypertension. DESIGN AND METHODS: We assessed the influence of the T-344C polymorphism of aldosterone synthase - the rate-limiting enzyme in aldosterone biosynthesis - on the structure of the left ventricle in young normotensive men. The population included 113 normotensive mid-European Caucasian men aged 18-40 years (mean 27 +/- 5 years). We also studied the association of -344T/C polymorphism of the CYP11B2 gene with the presence and severity of hypertension in 369 individuals, of whom 213 were hypertensive patients (139 controlled hypertensive, 74 resistant hypertensive) and 156 were healthy normotensive subjects. The genotype was assessed using polymerase chain reaction with subsequent cleavage with restriction enzyme HAEIII (restriction fragment length polymorphism method) and visualization with ethidium bromide. Plasma renin activity (PRA) and plasma...
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Cabrita, Brigite Ladeira. "Characterization and modulation of the Renin-Angiotensin System in Diabetic Retinopathy." Master's thesis, 2019. http://hdl.handle.net/10362/89766.
Full textAbstract:
Diabetes mellitus is a chronic disease whose numbers of affected individuals are substantially increasing. Diabetes-associated complications include Diabetic Retinopathy (DR), the main cause of visual impairment and blindness. DR is a progressive pathology affecting the retina, caused by chronic hyperglycaemia. From the several associated risk factors, hypertension has been considered a key player in DR. Renin-Angiotensin System (RAS) is the hormonal cascade responsible for the control of blood pressure. This system can be divided in two main axes: a deleterious one that promotes vasoconstriction, inflammation, angiogenesis and increased oxidative stress and a parallel axis known to counterbalance these effects. Both axes’ components have been identified in the eye and we have shown that the prejudicial axis is modulated by glucose.
In this work we aimed to characterize the expression of the RAS protective axis in retinal pigment epithelium (RPE) cells and evaluate the effects of its modulation by glucose and direct renin inhibition. The expression of Angiotensin-converting enzyme 2, Angiotensin (1-7) and Mas1 were detected in RPE cells. A decrease in the expression of these components was observed in high glucose conditions, showing a RAS imbalance. These results are supported by the results obtained in the retina of a type 1 diabetic animal, the Ins2Akita mouse.
RAS dysregulation triggers DR hallmarks such as oxidative stress and angiogenesis. Thus, RAS blockade can affect DR development and progression. When simulating RAS overactivation, expression of the protective components increased over time, pointing to an initial protective role that needs further investigation. When treating cells with a renin-blocker, aliskiren, decreased levels of Angiotensin-converting enzyme 2 and Mas1 were observed, probably caused by the non-formation of angiotensin peptides. Overall our results are indicative of an early effect of the protective arm of RAS in the glucose-induced RAS dysregulation.
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Shi, Yixuan. "Caractérisation du gène de l'enzyme de conversion de l'angiotensine-2 dans le rein diabétique et implication dans le développement de la néphropathie diabétique et de l'hypertension." Thèse, 2014. http://hdl.handle.net/1866/11828.
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De nombreuses études ont bien démontré que l’activation du système rénine-angiotensine (RAS) joue un rôle important dans le développement de l’hypertension et de la néphropathie diabétique (DN). La découverte de l’enzyme de conversion de l’angiotensine-2 (ACE2) et l’identification du récepteur MAS, spécifique pour l’angiotensine 1-7 (Ang 1-7), ont permis d’identifier deux nouveaux membres du RAS. L’axe ACE2/Ang 1-7/MAS contrebalance les effets de l’axe ACE/Ang II/AT1. Plusieurs évidences impliquent la contribution du RAS intrarénal dans la DN. Des études réalisées dans notre laboratoire avec des souris transgéniques surexprimant l’angiotensinogène de rat dans les cellules de leurs tubules proximaux rénaux (RPTCs) ont permis de démontrer l’importance du RAS intrarénal dans l’induction de l’hypertension et les dommages rénaux. Nous avons également observé que l’expression rénale de l’ACE2 et les niveaux urinaires d’ANG 1-7 sont plus faibles chez les souris Akita (diabète de type 1) et qu’un traitement avec des bloqueurs du RAS permet de normaliser l’expression de l’ACE2 et de prévenir le développement de l’hypertension dans le modèle des souris Akita. Dans un milieu diabétique, à la fois la glycémie et l’angiotensine II (Ang II) peuvent induire la génération des espèces réactives de l’oxygène (ROS), contribuant ainsi aux dommages rénaux. Afin d’explorer la relation entre les ROS, ACE2 et la DN, nous avons créé des souris Akita transgéniques surexprimant la catalase (Cat) dans les RPTCs, en croisant des souris Akita diabétique de type 1 à notre modèle de souris transgéniques surexprimant la Cat de rat dans les RPTCs. Dans une seconde étude, des souris Akita ont été traitées avec l’Ang 1-7 ou une combinaison d’Ang 1-7 et de son antagoniste, A779, afin d’étudier la relation entre l’action de l’Ang 1-7, l’hypertension systolique (sHTN), le stress oxydatif, les dommages rénaux, ACE2 et l’expression du récepteur Mas.
Nos résultats ont montré que la surexpression de Cat atténue le stress oxydatif rénal; prévient l’hypertension, améliore le taux de filtration glomérulaire, l’albuminurie, l’hypertrophie rénale, la fibrose tubulo-interstitielle et l’apoptose tubulaire; et supprime l’expression des gènes profibrotiques et proapoptotiques dans les RPTCs des souris Akita Cat-Tg lorsque comparées aux souris Akita. De plus, la surexpression de Cat dans les RPTC des souris Akita normalise l’expression rénale de l’ACE2 et les niveaux urinaires d’Ang 1-7.
D’autre part, l’administration d’Ang 1-7 prévient l’hypertension systémique, normalise le ratio albumine/créatinine urinaire et atténue l’hyperfiltration glomérulaire des souris Akita, sans affecter la glycémie sanguine. De plus, le traitement avec l’Ang 1-7 atténue aussi le stress oxydatif et l’expression de la NADPH oxydase, Agt, ACE, TGF-β1 (transforming growth factor-β1) et collagène IV, tout en augmentant l’expression de l’ACE2 et du récepteur Mas dans les reins des souris Akita. Ces effets sont renversés par la co-admininstration d’A779.
Ces résultats démontrent que la surexpression de Cat prévient l’hypertension et la progression de la néphropathie, en plus de mettre en lumière l’importance du stress oxydatif intrarénal et l’expression de l’ACE2 comme facteurs contribuant à l’hypertension et les dommages rénaux observés dans le diabète. En outre, nos données suggèrent que l’Ang 1-7 joue un rôle protecteur dans l’hypertension et les dommages aux RPTC dans le diabète, principalement en réduisant les voies de signalisations du stress oxydatif dans les reins et en normalisant l’expression de l’ACE2 et du récepteur Mas. Nos résultats indiquent aussi que l’Ang 1-7 pourrait agir comme un agent thérapeutique potentiel dans le traitement de l’hypertension systémique et les dommages rénaux observés dans le diabète. En conséquence, l’Ang 1-7 est responsable du rôle protecteur de l’ACE2 dans l’hypertension et la DN.It is well accepted that renin-angiotensin system (RAS) activation plays an important role in the development of hypertension and diabetic nephropathy (DN). With the discovery of angiotensin-converting enzyme-2 (ACE2) and recognition of MAS as the receptor of Angiotensin 1-7 (Ang 1-7), new players in RAS, ACE2/Ang 1-7/MAS axis, have been identified to counteract the effect of ACE/Ang II/ AT1 axis. Evidence implicates the intrarenal RAS’s contribution to DN. Previous studies from our laboratory using transgenic mice overexpressing rat Angiotensinogen (Agt) in their renal proximal tubular cells (RPTCs) have demonstrated the importance of the intrarenal RAS in renal damage and the induction of hypertension. We also recently observed that renal ACE2 expression and urinary Ang 1–7 were lower in type 1 diabetic Akita mice and that treatment with RAS blockers normalized ACE2 expression and prevented hypertension development in these Akita mice. In the diabetic milieu, both glycemia and angiotensin II (Ang II) can induce reactive oxygen species (ROS) generation, which contributes to kidney injury. To explore the relationship among ROS, ACE2 and DN, we created Akita transgenic mice overexpressing catalase (Cat) in RPTCs by crossbreeding type I diabetic Akita mice with our established transgenic mice overexpressing rat Cat in RPTCs. In another study, Akita mice were treated with Ang 1-7 or combination of Ang 1-7 and its antagonist, A779, to investigate the relations between Ang 1-7 action, systolic hypertension (sHTN), oxidative stress, kidney injury, ACE2 and Mas receptor expression. Our results showed that overexpression of Cat attenuated renal oxidative stress; prevented hypertension; ameliorated glomerular filtration rate, albuminuria, kidney hypertrophy, tubulointerstitial fibrosis, and tubular apoptosis; and suppressed profibrotic and proapoptotic gene expression in RPTCs of Akita Cat-Tg mice compared with Akita mice. Furthermore, overexpression of Cat in RPTCs of Akita mice normalized renal ACE2 expression and urinary Ang 1–7 levels. On the other hand, Ang 1-7 administration prevented systemic hypertension, normalized urinary albumin/creatinine ratio and attenuated glomerular hyperfiltration without affecting blood glucose levels in Akita mice. Furthermore, Ang 1-7 treatment also attenuated oxidative stress and the expression of NADPH oxidase 4, Agt, ACE, transforming growth factor-β1 (TGF-β1) and collagen IV, and increased the expression of ACE2 and Mas receptor in Akita mouse kidneys. These effects were reversed by co-administration of A779. These data demonstrated that Cat overexpression prevents hypertension and progression of nephropathy and highlight the importance of intrarenal oxidative stress and ACE2 expression contributing to hypertension and renal injury in diabetes. Furthermore, our data suggest that Ang 1-7 plays a protective role in hypertension and RPTC injury in diabetes, predominantly through decreasing renal oxidative stress-mediated signaling and normalizing ACE2 and Mas receptor expression. Our results also indicate Ang 1-7 as a potential therapeutic agent for treatment of systemic hypertension and kidney injury in diabetes. Therefore, Ang 1-7 mediates the major protective role of ACE2 in the hypertension and DN.