Repositório Institucional - Unifesp :: Navegando por Palavras-chave "renin-angiotensin system"

Navegando por Palavras-chave "renin-angiotensin system"

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Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia
(Amer Physiological Soc, 2016) Rosa, Rodolfo Mattar [UNIFESP]; Colucci, Juliana Almada [UNIFESP]; Yokota, Rodrigo [UNIFESP]; Moreira, Roseli Peres [UNIFESP]; Aragao, Danielle Sanches [UNIFESP]; Ribeiro, Amanda Aparecida [UNIFESP]; Arita, Danielle Yuri [UNIFESP]; Mizuno Watanabe, Ingrid Kazue [UNIFESP]; Palomino, Zaira [UNIFESP]; Cunha, Tatiana Sousa [UNIFESP]; Casarini, Dulce Elena [UNIFESP]
Sepsis is an uncontrolled systemic inflammatory response against an infection and a major public health issue worldwide. This condition affects several organs, and, when caused by Gram-negative bacteria, kidneys are particularly damaged. Due to the importance of renin-angiotensin system (RAS) in regulating renal function, in the present study, we aimed to investigate the effects of endotoxemia over the renal RAS. Wistar rats were injected with Escherichia coli lipopolysaccharide (LPS) (4 mg/kg), mimicking the endotoxemia induced by Gram-negative bacteria. Three days after treatment, body mass, blood pressure, and plasma nitric oxide (NO) were reduced, indicating that endotoxemia triggered cardiovascular and metabolic consequences and that hypotension was maintained by NO-independent mechanisms. Regarding the effects in renal tissue, inducible NO synthase (iNOS) was diminished, but no changes in the renal level of NO were detected. RAS was also highly affected by endotoxemia, since renin, angiotensin-converting enzyme (ACE), and ACE2 activities were altered in renal tissue. Although these enzymes were modulated, only angiotensin (ANG) II was augmented in kidneys
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ANGIOTENSIN III MODULATES the NOCICEPTIVE CONTROL MEDIATED BY the PERIAQUEDUCTAL GRAY MATTER
(Elsevier B.V., 2009-12-15) Pelegrini-da-Silva, A.; Rosa, E.; Guethe, L. M.; Juliano, M. A. [UNIFESP]; Prado, W. A.; Martins, A. R.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type I (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vi) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vIPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that. Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vIPAG reduced incision allodynia. Incubation of Ang II with punches of vIPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vIPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vIPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vIPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vIPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vIPAG can be ascribed preponderantly to Ang III. (C) 2009 IBRO. Published by Elsevier B.V. All rights reserved.
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Angiotensinogen and angiotensin converting enzyme gene polymorphisms and the risk of bipolar affective disorder in humans
(Elsevier B.V., 2000-10-27) Meira-Lima, IV; Pereira, A. C.; Mota, GFA; Krieger, J. E.; Vallada, H.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
A possible participation of the renin-angiotensin system (RAS) components with mood disturbances has been suggested in both animal and pharmacological models. in this cross-sectional study, we examined the association between functional polymorphisms in the angiotensin converting enzyme (ACE) and angiotensinogen (AGI) genes in 115 bipolar affective disorder (BPAD) patients and 323 healthy control subjects. the ACE I/D variant did not show any difference in allelic frequencies and genotypic distribution between the groups. in contrast, when studying the AGT M235T polymorphism we found that the M allele was more frequently observed in BPAD patients than in controls (chi (2) = 6.766, d.f. = 1, P = 0.009). Using multivariate logistic models the strongest odds ratio resulted from a dominant genetic model (OR = 3.0; CI (95%) 1.7-5.3] Our data suggest an association between the AGT M235 genotype and increased susceptibility for BPAD in these Brazilian patients. These findings are consistent with the hypothesis that the RAS system plays a role in regulating the mood (C) 2000 Published by Elsevier Science Ireland Ltd.
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Autonomic control in rats with overactivity of tissue renin-angiotensin or kallikrein-kinin system
(Elsevier B.V., 2005-07-15) Ribeiro, J. M.; Santos, RAS; Pesquero, J. B.; Bader, M.; Krieger, E. M.; Universidade de São Paulo (USP); Universidade Federal de Minas Gerais (UFMG); Max Delbruck Ctr Mol Med; Universidade Federal de São Paulo (UNIFESP)
The renin-angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system and the kallikrein-kinin system (KKS) appears to counteract most of the RAS effects. in this study the vagal and the sympathetic influences on the heart rate and the baroreflex control of the heart rate were evaluated in transgenics rats with human tissue kallikrein gene expression [TGR(hKLK1)], and transgenics rats with tissue renin overexpression [TGR(mREN2)27]. Heart rate was similar in all groups but mean arterial pressure was higher in mREN2 rats than in kallikrein and control rats (149 +/- 4 vs. 114 +/- 3 vs. 113 +/- 3 mm Hg, respectively). the intrinsic heart rate was lower in mREN2 rats than in kallikrein and control rats (324 +/- 5 vs. 331 +/- 3 vs. 343 +/- 7 bpm). the HR response to atropine was similar but the response to propranolol was higher in kallikrein rats than control group (61 +/- 7 vs. 60 +/- 9 vs. 38 +/- 7 bpm, respectively). the vagal tonus was lower in mREN2 than in SD and hKAL rats (18 +/- 3 vs. 40 +/- 6 vs. 35 +/- 6 bpm) whereas the sympathetic tonus was higher in kallikrein rats (118 +/- 7 vs. 96 +/- 1 vs. 81 +/- 9 bpm in the mREN2 and SD rats), respectively. Baroreflex sensitivity to bradycardic responses was attenuated in mREN2 rats (0.37 +/- 0.05 vs. 1.34 +/- 0.08 vs. 1.34 +/- 0.13 bpm/mm Hg) while the tachycardic responses were unchanged. the bradycardic responses to electrical stimulation of the vagal nerve were depressed in both renin and kallikrein rats (129 +/- 47 vs. 129 +/- 22 vs. 193 +/- 25 bpm in control group in response to 32 Hz). in conclusion: 1. the rats with overexpression of renin showed decreased intrinsic heart rate and impairment of vagal function, characterized by decreased vagal tonus, reduced response of HR to electrical stimulation of vagus nerve, and depressed reflex bradycardia provoked by increases of blood pressure. 2. the rats with overexpression of kallikrein showed an increase of sympathetic activity that regulates the heart rate, characterized by increased HR response to propranolol and increased sympathetic tonus, accompanied by decreased bradycardic responses to electrical vagal stimulation. (c) 2005 Elsevier B.V. All rights reserved.
Acesso aberto (Open Access)
Caracterização fisiopatológica do sistema renina-angiotensina durante o status epilepticus induzido pela pilocarpina em camundongos transgênicos que expressam tonina de rato
(Universidade Federal de São Paulo (UNIFESP), 2013-12-20) Iha, Higor Alves [UNIFESP]; Mazzacoratti, Maria da Graca Naffah Mazzacoratti [UNIFESP]; Gouveia, Telma Luciana Furtado Gouveia; http://lattes.cnpq.br/5872912520546019; http://lattes.cnpq.br/3202325307358102; http://lattes.cnpq.br/7202294193275511; Universidade Federal de São Paulo (UNIFESP)
Objectives: To evaluate the influence of pilocarpine induced long-term convulsive seizure in transgenic mice with overexpressed plasma and brain Ang II. Methods: Using a 320mg/kg pilocarpine dose to induce SE. Following the injection protocol of CAVALHEIRO (1995). We conducted an investigation of both strains (TGM (rTon) and WT C57Black/6) of the following groups: a) saline group; b) 3 hour in SE group; and c) Tonic-clonic seizure group. The last group was created upon the greater incidence of such crises in rTon when compared with WT. During the SE, we accessed several parameters such as latency for the first seizure, tonic-clonic seizure susceptibility and mortality. In their hippocampi was assessed by western-blot, real-time RT-PCR, respectively, protein and RNAm expression levels of AT1, AT2, B1 and B2 receptors as well as of the ACE ACE2, iNOS and eNOS enzymes. The same was made to AT1 receptor in heart. It was also assessed the enzymatic activity of hippocampal, cardiac and plasmatic ECA. Results: In an assessment of how both strains reacted to the pilocarpine induced SE we found no difference on first seizure latency time, but a significant higher frequency of death during the generalized tonic-clonic seizure in rTon mice, 66% in rTon and 34% in WT. In RAS, KKS and NO analyzed parameters we found in studied mice groups strain comparison that rTon showed: a) Saline group: in mRNA hippocampal expression, greater transcript level for iNOS and lower for B1 receptor, in protein quantifying, greater for hippocampal AT1 receptor and lower for cardiac AT1 receptor, thereafter, on ECA enzymatic activity evaluation, greater in hippocampi and heart a and on ACE activity, in heart on AT1 receptor protein levels and in plasma on ACE activity; b) in Tonic-Clonic group: mRNA levels were reduced transcripts of eNOS and iNOS, protein quantification showed raised in hippocampi raised ECA2 and lowered B1 receptor and in heart raised AT1 receptor, thereafter, in ECA enzymatic activity assessment, increased in hippocampal and in plasmatic forms. c) 3h of SE group: in hippocampi mRNA levels were upkeeped for ECA transcript, raised for ECA2 and eNOS transcript and reduced for iNOS transcript, protein analysis showed greater raised hippocampal and heart AT1 receptor and hippocampal lowered B2 receptor. Thereafter, on ECA enzymatic activity evaluation, showed raised activity on hippocampal and plasmatic forms. Conclusion: Transgenic mice showed in assessed tissues differences on RAS, KKS and iNOS expression. These differences resulted in a differentiated response to pilocarpine induced seizure in RAS, KKS, iNOS and eNOS which culminated in a greater propensity to tonic-clonic seizures and greater frequency of death throughout the SE, but didn´t affected the latency period for the first seizure.
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Cardiac-specific suppression of NF-kappa B signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system
(Amer Physiological Soc, 2014-10-01) Thomas, Candice M.; Yong, Qian Chen; Rosa, Rodolfo M. [UNIFESP]; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E. [UNIFESP]; Jones, W. Keith; Gupta, Sudhiranjan; Baker, Kenneth M.; Kumar, Rajesh; Texas A&M Hlth Sci Ctr; Baylor Scott & White Hlth; Cent Texas Vet Hlth Care Syst; Universidade Federal de São Paulo (UNIFESP); Loyola Univ Chicago
Activation of NF-kappa B signaling in the heart may be protective or deleterious depending on the pathological context. in diabetes, the role of NF-kappa B in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-kappa B modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated I kappa B-alpha in the heart (3M mice), which prevented activation of canonical NF-kappa B signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. in contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. in diabetic WT mice, an increase in the phospholamban/sarco(endo) plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. in conclusion, these results demonstrate that inhibition of NF-kappa B signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system.
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Diversity of pathways for intracellular angiotensin II synthesis
(Lippincott Williams & Wilkins, 2009-01-01) Kumar, Rajesh; Boim, Mirian A. [UNIFESP]; Texas A&M Hlth Sci Ctr; Scott & White Mem Hosp & Clin; Cent Texas Vet Healthcare Syst; Universidade Federal de São Paulo (UNIFESP)
Purpose of reviewThe renin-angiotensin system (RAS) has undergone continuous advancement since the initial identification of renin as a pressor agent. Traditionally considered a circulatory system, the RAS is now known to exist as a tissue system as well. Recently, the tissue RAS has been further categorized as intracellular and extracellular. Owing to the unique location, the intracellular RAS encompasses new components, such as cathepsin D and chymase, which participate in intracellular angiotensin (Ang) II synthesis. in this review, evidence of the intracellular RAS and the mechanism of Ang II synthesis in various cell types will be discussed.Recent findingsA physiological role for intracellular Ang II in vascular and cardiac cells has recently been demonstrated. Evidence of intracellular Ang II generation has been shown in several cell types, particularly cardiac, renal, and vascular. Importantly, intracellular synthesis of Ang II is more prominent in hyperglycemic conditions and generally involves angiotensin-converting enzyme-dependent and angiotensin-converting enzyme-independent mechanisms,SummaryThere is significant diversity in the mechanism of intracellular synthesis of Ang II in various cell types and pathological conditions. These observations suggest that a therapeutic intervention to block the RAS should take into consideration the nature of the disorder and the cell type involved.
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Escherichia coli lipopolysaccharide inhibits renin activity in human mesangial cells
(Nature Publishing Group, 2006-03-01) Almeida, W. S.; Maciel, T. T.; Di Marco, Giovana Seno [UNIFESP]; Casarini, Dulce Elena [UNIFESP]; Campos, Alexandre Holthausen [UNIFESP]; Schor, Nestor [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
Hyperactivation of systemic renin-angiotensin system (RAS) during sepsis is well documented. However, the behavior of intrarenal RAS in the context of endotoxemia is yet to be defined. the present study evaluates the direct effect of Escherichia coli lipopolysaccharide (LPS) on immortalized human mesangial cell (HMC) RAS. Quiescent HMC were incubated with vehicle or LPS (1-100 mu g/ml), and levels of angiotensin I and II (Ang I and II) and their metabolites were analyzed by high-performance liquid chromatography. in addition, angiotensin-converting enzyme (ACE) and renin activity were also investigated. Cell lysate and extracellular medium levels of Ang II were rapidly reduced (1 h) in a time- and concentration-dependent manner, reaching a significant -9 fold-change (P < 0.001) after 3 h of LPS incubation. Similar results were obtained for Ang I levels (-3 fold-change, P < 0.001). We ruled out Ang I and II degradation, as levels of their metabolic fragments were also significantly decreased by LPS. ACE activity was slightly increased following LPS incubation. On the other hand, renin activity was significantly inhibited, as Ang I concentration elevation following exogenous angiotensinogen administration was blunted by LPS (-60% vs vehicle, P < 0.001). Renin and angiotensinogen protein levels were not affected by LPS according to Western blot analysis. Taken together, these data demonstrate for the first time that LPS significantly downregulates HMC RAS through inhibition of renin or renin-like activity. These findings are potentially related to the development of and/or recovery from acute renal failure in the context of sepsis.
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Estudo do sistema renina-angiotensina em animais durante a epileptogênese
(Universidade Federal de São Paulo (UNIFESP), 2014-05-12) Brito, Joise Marques Vieira de [UNIFESP]; Mazzacoratti, Maria da Graca Naffah Mazzacoratti [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
Introduction: Recent data have associated the renin-angiotensin system (RAS) to some types of epilepsy. A previous study from our group showed an increased XVIII expression of angiotensin II (Ang II) receptors (AT1 and AT2 ) in the cortex and hippocampus of patients with Temporal Lobe Epilepsy (TLE).Objective: In order to verify the role of these components of RAS during epileptogenesis the present work studied the gene and protein expression of AT1, AT2 and Mas receptors, angiotensin converting enzyme (ACE) and the concentration of important peptides (Angl, Ang II and Ang 1-7), in the hippocampus of rats in pilocarpine-induced epilepsy. Methods: The animals were subjected to the experimental model with the injection of pilocarpine (350 mg / kg ip) or saline (control group). The animals were grouped according to the phase of the model: acute (status epilepticus), silent (seizure free), chronic (spontaneous recurrent seizures) and saline (control). HPLC techniques were performed to determine the concentration of Ang I, Ang II and Ang 1-7. RT-PCR, Western blotting and immunohistochemistry was used to evaluate the gene and protein expression of ACE and AT1, AT2 and Mas receptors levels and distribution. In the chronic phase the seizure frequency was assessed by video monitoring in the same group of rats, before and after treatment with perindopril (ACE-inhibitor). Changes in systolic blood pressure, neuronal death and mossy fiber sprouting after treatment with perindopril were also evaluated. Statistical analysis one-way ANOVA followed by Tukey-Kramer test was performed to verify the HPLC assays and RT-PCR. Unpaired Student t test was used to compare the results of Western blotting, quantification of the frequency of seizures and systolic blood pressure variation. p <0.05 was accepted. Results: Different concentration of Angl, AngII and Ang1-7 were founded on the 3 phases of this model, as well as AT1, AT2 and Mas receptor and enzyme ACE levels. Conclusion: Ang I appears to be converted to Ang II and Ang 1-7 at the hippocampus during the process of epileptogenesis. The increase in the concentration of Ang II and AT1 receptor in the chronic phase may be related to the generation of spontaneous seizures, since ACE-inhibitor was able to reduce the seizures frequency. High expression levels of Ang1-7, which would have antagonistic action of AngII, and the increased Mas receptor, in the silent phase, suggests that this peptide is involved in seizure blocking. Levels of Ang II and its receptors ( AT1 and AT2 ) was increased in the chronic phase , confirming the data reported by our group in another study , which showed increased expression of these receptors in hippocampal tissue from TLE patients already installed. The reduction of Ang II by perindopril induced a decrease in seizure frequency (chronic phase), reduced blood pressure and minimized the development of mossy fiber sprouting. However, perindopril was not able to modify the loss of hippocampal neurons. The results suggest that this antihypertensive can be beneficial in the treatment of epilepsy.
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Genetically altered animals in the study of the metabolic functions of peptide hormone systems
(Lippincott Williams & Wilkins, 2008-01-01) Mori, Marcelo Alves da Silva [UNIFESP]; Bader, Michael [UNIFESP]; Pesquero, João Bosco [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Max Delbruck Ctr Mol Med
Purpose of reviewHere we review the use of genetically altered animals to address the roles of peptide hormone systems in the modulation of energy homeostasis. Despite the disseminated use of transgenic techniques to establish the functional relevance of several peptide hormone systems, we focus on two multifunctional systems, the renin-angiotensin and the kallikrein-kinin systems. Initially, we explored the background information supporting the functional aspects of these systems, followed by novel knowledge obtained with the phenotypic characterization of genetically altered animals.Recent findingsA role for the renin-angiotensin system in the regulation of adiposity and glucose metabolism has been suggested. Studies using genetically altered animals not only confirmed the physiological relevance of angiotensin 11 in the control of energy homeostasis, but also revealed that the adipose tissue renin-angiotensin system participates in the endocrine modulation of cardiovascular and renal function. On the other hand, the involvement of the kallikrein-kinin system with metabolic processes was not so obvious. Recent reports using genetically altered animals, however, provided strong evidence to support an important role for kinins in the control of glucose homeostasis and energy balance.SummaryHere we present examples of how genetically altered animals contribute to a final postulation of the physiological roles of certain hormone systems, bringing new insights into the field.
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High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells
(Amer Physiological Soc, 2004-06-01) Vidotti, D. B.; Casarini, D. E.; Cristovam, P. C.; Leite, C. A.; Schor, N.[UNIFESP]; Boim, M. A.; Universidade Federal de São Paulo (UNIFESP)
Increased intrarenal renin-angiotensin system activity contributes to diabetic nephropathy. ANG II generation in mesangial cells (MC) is increased by high-glucose (HG) exposure. This study assessed the mechanisms involved in the glucose-induced ANG II generation in rat MC. Under basal conditions, MC mainly secreted prorenin. HG decreased prorenin secretion and induced a striking 30-fold increase in intracellular renin activity. After 72 h of HG exposure, only the mRNA levels for angiotensinogen and angiotensin-converting enzyme (ACE) were significantly elevated. However, after shorter periods of 24 h of HG stimulation the mRNA levels of the enzymes prorenin and cathepsin B, besides that for ACE, were significantly increased. the results suggest that the HG-induced increase in ANG II generation in MC results from an increase in intracellular renin activity mediated by at least three factors: a time-dependent stimulation of ( pro) renin gene transcription, a reduction in prorenin enzyme secretion, and an increased rate of conversion of prorenin to active renin, probably mediated by cathepsin B. the increase in angiotensinogen mRNA in parallel to increased renin activity indicates that HG also increased the availability of the renin substrate. the consistent upregulation of ACE mRNA suggests that, besides renin, ACE is directly involved in the increased mesangial ANG II generation induced by HG.
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Improved cardiovascular autonomic modulation in transgenic rats expressing an Ang-(1-7)-producing fusion protein
(Canadian Science Publishing, Nrc Research Press, 2017) Dartora, Daniela Ravizzoni; Irigoyen, Maria-Claudia; Casali, Karina Rabello [UNIFESP]; Moraes-Silva, Ivana C.; Bertagnolli, Mariane; Bader, Michael; Santos, Robson A. S.
Angiotensin-(1-7) counterbalances angiotensin II cardiovascular effects. However, it has yet to be determined how cardiovascular autonomic modulation may be affected by chronic and acute elevation of Ang-(1-7). Hemodynamics and cardiovascular autonomic profile were evaluated in male Sprague-Dawley (SD) rats and transgenic rats (TGR) overexpressing Ang-(1-7) [TGR(A1-7) 3292]. Blood pressure (BP) was directly measured while cardiovascular autonomic modulation was evaluated by spectral analysis. TGR received A-779 or vehicle and SD rats received Ang-(1-7) or vehicle and were monitored for 5 h after i.v. administration. In another set of experiments with TGR, A-779 was infused for 7 days using osmotic mini pumps. Although at baseline no differences were observed, acute administration of A-779 in TGR produced a marked long-lasting increase in BP accompanied by increased BP variability (BPV) and sympathetic modulation to the vessels. Likewise, chronic administration of A-779 with osmotic mini pumps in TGR increased heart rate, sympathovagal balance, BPV, and sympathetic modulation to the vessels. Administration of Ang-(1-7) to SD rats increased heart rate variability values in 88% accompanied by 8% of vagal modulation increase and 18% of mean BP reduction. These results show that both acute and chronic alteration in the Ang-(1-7)-Mas receptor axis may lead to important changes in the autonomic control of circulation, impacting either sympathetic and (or) parasympathetic systems.
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Increased blood pressure in the offspring of diabetic mothers
(Amer Physiological Soc, 2005-05-01) Wichi, Rogerio B. [UNIFESP]; Souza, Silvia B. [UNIFESP]; Casarini, Dulce E. [UNIFESP]; Morris, Mariana; Barreto-Chaves, Maria Luiza; Irigoyen, Maria Claudia; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Wright State Univ
Studies were conducted in rats to determine the effect of maternal diabetes and the consequent hyperglycemia on cardiovascular function in the offspring. Diabetes was induced in pregnant Wistar rats through streptozotocin injection ( 50 mg/kg). Cardiovascular parameters were measured in 2-mo-old offspring animals of diabetic ( OD, n = 12) and control rats (OC, n = 8). Arterial pressure (AP), heart rate (HR), baroreflex sensitivity, and vascular responsiveness to phenylephrine (PH) and sodium nitroprusside (SN) were measured. Angiotensin-converting enzyme ( ACE) activity in heart, kidney, and lung was determined. OD rats exhibited increases in systolic AP ( 138 +/- 8 vs. 119 +/- 6 mmHg, OD vs. OC), with no change in HR ( 342 +/- 21 vs. 364 +/- 39 beats per minute (bpm), OD vs. OC). the reflex tachycardia elicited by SN was reduced in OD rats, as indicated by the slope of the linear regression ( - 2.2 +/- 0.4 vs. - 3.6 +/- 0.8 bpm/mmHg, OD vs. OC). Vascular responsiveness to PH was increased 63% in OD rats compared with OC. OD rats showed increases in ACE activity in heart, kidney, and lung (1.13 +/- 0.24, 3.04 +/- 0.86, 40.8 +/- 8.9 vs. 0.73 +/- 0.19, 1.7 +/- 0.45, 28.1 +/- 6 nmol His-Leu center dot min(-1) mg protein(-1), OD vs. OC). Results suggest that diabetes during pregnancy affects cardiovascular function in offspring, seen as hypertension, baroreflex dysfunction, and activation of tissue renin-angiotensin system.
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Interactions between angiotensin-(1-7), kinins, and angiotensin II in kidney and blood vessels
(Lippincott Williams & Wilkins, 2001-09-01) Santos, RAS dos; Passaglio, K. T.; Pesquero, João Bosco [UNIFESP]; Bader, Michael [UNIFESP]; Silva, ACSE; Universidade Federal de Minas Gerais (UFMG); Universidade Federal de São Paulo (UNIFESP); Max Delbruck Ctr Mol Med
The heptapeptide angiotensin (Ang)-(1-7) is currently considered one of the biologically active end products of the renin-angiotensin system. The formation of Ang-(1-7) by pathways independent of Ang II generation, the selectivity of its actions, and its peculiar property of exhibiting effects that are partially opposite of those of the parent compound, Ang II, confer a unique biochemical and functional profile to this peptide. In this article, we will review novel aspects of the biological actions of Ang-(1-7), dealing with its interaction with Ang II and kinins, especially in the kidney and blood vessels.
Acesso aberto (Open Access)
Ligand-induced endocytosis and nuclear localization of angiotensin II receptors expressed in CHO cells
(Associação Brasileira de Divulgação Científica, 2001-09-01) Merjan, A.j. [UNIFESP]; Kanashiro, Celia Akemi [UNIFESP]; Krieger, Jose Eduardo; Han, Sang Won [UNIFESP]; Paiva, Antonio Cechelli de Mattos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)
A construct (AT1R-NF) containing a Flag sequence added to the N-terminus of the rat AT1 receptor was stably expressed in Chinese hamster ovary cells and quantified in the cell membrane by confocal microscopy after reaction with a fluorescein-labeled anti-Flag monoclonal antibody. Angiotensin II bound to AT1R-NF and induced endocytosis with a half-time of 2 min. After 60-90 min, fluorescence accumulated around the cell nucleus, suggesting migration of the ligand-receptor complex to the nuclear membrane. Angiotensin antagonists also induced endocytosis, suggesting that a common step in the transduction signal mechanism occurring after ligand binding may be responsible for the ligand-receptor complex internalization.
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Low birth weight in response to salt restriction during pregnancy is not due to alterations in uterine-placental blood flow or the placental and peripheral renin-angiotensin system
(Elsevier B.V., 2008-09-03) Leandro, Sandra Marcia; Shinohara Furukawa, Luzia Naoko; Massola Shimizu, Maria Heloisa; Casarini, Dulce Elena [UNIFESP]; Seguro, Antonio Carlos; Patriarca, Giuliana; Coelho, Michella Soares; Dolnikoff, Miriam Sterman [UNIFESP]; Heimann, Joel Claudio; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
A number of studies conducted in humans and in animals have observed that events occurring early in life are associated with the development of diseases in adulthood. Salt overload and restriction during pregnancy and lactation are responsible for functional (hemodynamic and hormonal) and structural alterations in adult offspring. Our group observed that lower birth weight and insulin resistance in adulthood is associated with salt restriction during pregnancy On the other hand, perinatal salt overload is associated with higher blood pressure and higher renal angiotensin II content in adult offspring. Therefore, we hypothesised that renin-angiotensin system (RAS) function is altered by changes in sodium intake during pregnancy. Such changes may influence fetoplacental blood flow and thereby fetal nutrient supply, with effects on growth in utero and, consequently, on birth weight. Female Wistar rats were fed low-salt (LS), normal-salt (NS), or high-salt (HS) diet, starting before conception and continuing until day 19 of pregnancy, Blood pressure, heart rate, fetuses and dams' body weight, placentae weight and litter size were measured on day 19 of pregnancy. Cardiac output, uterine and placental blood flow were also determined on day 19. Expressions of renin-angiotensin system components and of the TNF-alpha gene were evaluated in the placentae. Plasma renin activity (PRA) and plasma and tissue angiotensin-converting enzyme (ACE) activity, as well as plasma and placental levels of angiotensins I, II, and 1-7 were measured. Body weight and kidney mass were greater in HS than in NS and LS dams. Food intake did not differ among the maternal groups. Placental weight was lower in LS dams than in NS and HS dams. Fetal weight was lower in the US group than in the NS and HS groups. the PRA was greater in IS dams than in NS and HS dams, although ACE activity (serum, cardiac, renal, and placental) was unaffected by the level of sodium intake. Placental levels of angiotensins I and II were lower in the HS group than in the ISIS and IS groups. Placental angiotensin receptor type 1 (AT(1)) gene expression and levels of thiobarbituric acid reactive substances (TBARS) were higher in HS dams, as were uterine blood flow and cardiac output. the degree of salt intake did not influence plasma sodium, potassium or creatinine. Although fractional sodium excretion was higher in HS dams than in NS and LS dams, fractional potassium excretion was unchanged. in conclusion, findings from this study indicate that the reduction in fetal weight in response to salt restriction during pregnancy does not involve alterations in uterine-placental perfusion or the RAS. Moreover, no change in fetal weight is observed in response to salt overload during pregnancy. However, salt overload did lead to an increase in placental weight and uterine blood flow associated with alterations in maternal plasma and placental RAS. Therefore, these findings indicate that changes in salt intake during pregnancy lead to alterations in uterine-placental perfusion and fetal growth. (C) 2008 Elsevier Inc. All rights reserved.
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Mesenchymal stem cells and chronic renal artery stenosis
(Amer Physiological Soc, 2016) Oliveira-Sales, Elizabeth B. [UNIFESP]; Boim, Mirian A. [UNIFESP]
Renal artery stenosis is the main cause of renovascular hypertension and results in ischemic nephropathy characterized by inflammation, oxidative stress, microvascular loss, and fibrosis with consequent functional failure. Considering the limited number of strategies that effectively control renovascular hypertension and restore renal function, we propose that cell therapy may be a promising option based on the regenerative and immunosuppressive properties of stem cells. This review addresses the effects of mesenchymal stem cells (MSC) in an experimental animal model of renovascular hypertension known as 2 kidney-1 clip (2K-1C). Significant benefits of MSC treatment have been observed on blood pressure and renal structure of the stenotic kidney. The mechanisms involved are discussed.
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Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia
(Bentham Science Publ Ltd, 2018) de Oliveira, Fabricio Ferreira [UNIFESP]; Chen, Elizabeth Suchi [UNIFESP]; Smith, Marilia Cardoso [UNIFESP]; Ferreira Bertolucci, Paulo Henrique [UNIFESP]
Background: While the angiotensin-converting enzyme degrades amyloid-beta, angiotensin-converting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer's disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 - C (44.6% heterozygotes) and 0.345 for rs4291 - T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 - T and rs4291 - A, or for APOE4- carriers of rs1800764 - T or rs4291 - T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.
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Role of PGI(2) and effects of ACE inhibition on the bradykinin potentiation by angiotensin-(1-7) in resistance vessels of SHR
(Elsevier B.V., 2005-04-15) Fernandes, L.; Fortes, Z. B.; Casarini, D. E.; Nigro, D.; Tostes, RCA; Santos, RAS; Carvalho, MHC de; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Universidade Federal de Minas Gerais (UFMG)
The present study determined the participation of PGI(2) in the angiotensin-(1-7) [Ang-(1-7)libradykinin (BK) interaction, in the presence and absence of Angiotensin Converting Enzyme (ACE) inhibition, trying to correlate it with tissue levels of both peptides. the isolated mesenteric arteriolar bed of Spontaneously Hypertensive Rats (SHR) was perfused with Krebs or Krebs plus enalaprilat (10 DM), and drugs were injected alone or in association. BK (10 nM)-induced relaxation was potentiated by Ang-(1-7) (2.2 mug) in the presence or absence of enalaprilat. Ang-(1-7) receptor blockade [A-779 (4.8 mug)] did not interfere with the BK effect in preparations perfused with normal Krebs, but reversed the increased BK relaxation observed after ACE inhibition. PGI(2) release by mesenteric vessels was not altered by BK or Ang-(1-7) alone, but was increased when both peptides were injected in association, in the absence or in the presence of enalaprilat. ACE inhibition caused a 2-fold increase in the BK tissue levels, and a significant decrease in the Ang-(1-7) values. We conclude that endogenous Ang-(1-7) has an important contribution to the effect of ACE inhibitors participating in the enhancement of BK response. the mechanism of Ang-(1-7) potentiating effect probably involves an increased production of PGI(2). Our results suggest that a different enzymatic pathway (non-related to ACE) is involved in the local Ang-(1-7) metabolism. (C) 2004 Elsevier B.V. All rights reserved.
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Role of the kallikrein-kinin system in Ang-(1-7)-induced vasodilation in mesenteric arterioles of Wistar rats studied in vivo-in situ
(Elsevier B.V., 2006-07-01) Marangoni, R. A.; Carmona, A. K.; Passaglia, RCAT; Nigro, D.; Fortes, Z. B.; Carvalho, MHC de; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
Angiotensin-(1-7) [Ang-(1-7)], exerts a variety of actions in the cardiovascular system, with an important effect being vasodilation. in this work, we investigated the relationship between the vasodilatory activity of Ang-(1-7) and the kallikrein-kinin system. Intravital microscopy was used to study the vasodilation caused by Ang-(1-7) in the mesenteric vascular bed of anesthetized Wistar rats. the topical application of Ang-(1-7) caused vasodilation of mesenteric arterioles that was reduced by A-779, JE 049 and peptidase inhibitors (aprotinin, SBTI, PKSI 527, E-64, PMSF). These results indicated that the vasodilation induced by Ang-(1-7) in the mesenteric arterioles of Wistar rats was heavily dependent on the activation of kallikrein and subsequent kinin formation. (c) 2006 Published by Elsevier Inc.

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