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1.
Toxicol Lett ; 321: 44-53, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811911

RESUMO

This study was aimed to investigate the effect of prenatal ethanol exposure (PEE) on the susceptibility of offspring rats to glomerulosclerosis and to explore the mechanism. Pregnant Wistar rats were intragastrically administered ethanol (4g/kg·d) from gestational day (GD) 9 to GD 20, and the control group was given equal volume of normal saline. The offspring rats were all fed with high-fat diet after weaning, and were sacrificed at postnatal week 24 (PW24). The results revealed that the adult offspring kidneys in the male and female PEE groups exhibited higher glomerulosclerosis index and interstitial fibrosis index compared with the high-fat diet control groups, accompanied by elevated serum creatinine level. The protein expression of Nephrin and WT1, which were the marker genes of podocytes, was significantly decreased, whereas the protein expression of desmin and α-SMA, the marker genes of mesenchymal cells, was remarked enhanced in the male and female PEE groups. Compared with the high-fat diet control groups, the mRNA and protein expressions of renal angiotensin II receptor type 2 (AT2R) were decreased in the male PEE group, but increased in the female PEE group. PEE increased the mRNA and protein expressions of glucocorticoid (GC) activation system and inhibited the expression of insulin-like growth factor 1 (IGF1) signaling pathway in male offspring kidney; on the contrary, in female offspring kidney, PEE inhibited the mRNA and protein expression of glucocorticoid activation system and increased the expression of IGF1 signaling pathway. Taken together, PEE increased the susceptibility of the adult offspring to glomerulosclerosis, and the programming of renal AT2R or GC-IGF1 is respectively involved in the toxicity of PEE to the male or female offspring.


Assuntos
Dieta Hiperlipídica , Etanol/toxicidade , Glomerulonefrite/etiologia , Glomérulos Renais/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Fibrose , Regulação da Expressão Gênica , Idade Gestacional , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Gravidez , Ratos Wistar , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/genética
2.
Hypertension ; 74(4): 967-974, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378106

RESUMO

The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-ß-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ERß upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ERα protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ERß bound in the pregnant state. ERα protein levels were similar but higher ERß protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ERα to the AT2R promoter in the nonpregnant state and ERß to the AT2R promoter in pregnancy; however, only ERß recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ERß (not ERα) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ERß (not ERα) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ERß in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.


Assuntos
Células Endoteliais/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Artéria Uterina/efeitos dos fármacos , Animais , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Estradiol/sangue , Feminino , Gravidez , Ratos , Regulação para Cima/efeitos dos fármacos , Artéria Uterina/metabolismo
3.
Mol Cell Biochem ; 461(1-2): 195-204, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31414336

RESUMO

Recent studies on mice with null mutation of the angiotensin type 2 receptor (AT2R) gene have implicated the involvement of AT2R in regulating adipocyte size and obesity, a major risk factor for metabolic syndrome. However, the outcome from these studies remains inconclusive. Therefore, current study was designed to test whether pharmacological activation of AT2R regulates adiposity and lipid metabolism. Male mice (5-weeks old) were pre-treated with vehicle or AT2R agonist (C21, 0.3 mg/kg, i.p., daily, for 4 days) and fed normal diet (ND). Then these animals were subdivided into ND and high-fat diet (HFD) regimen and concomitantly treated with vehicle or C21 through day 14. Vehicle-treated HFD-fed mice demonstrated an increase in epididymal white adipose tissue (eWAT) weight and adipocyte size, which were associated with increased eWAT expression of the lipogenic regulators, fatty acid binding protein and fatty acid synthase, decreased expression of adipose triglyceride lipase and increased expression of hormone-sensitive lipase. Interestingly, C21 pre-treatment altered HFD-induced changes in lipogenic and lipolytic regulators. C21 pre-treatment prevented decrease in expression of uncoupler protein-1 in brown adipose in HFD-fed mice, which was associated with increased core temperature. In addition, C21 pre-treatment ameliorated plasma-free fatty acids, triglycerides, insulin and tumor necrosis factor-α in HFD-fed mice. Ex-vivo study in isolated primary epididymal adipocytes revealed that C21 inhibits long chain fatty acid transporter, via a nitric oxide synthase/guanylate cyclase/protein kinase G-dependent pathway. Collectively, we propose pharmacological activation of AT2R regulates fatty acid metabolism and thermogenesis and prevents HFD-induced adiposity in mice.


Assuntos
Adiposidade , Metabolismo dos Lipídeos , Receptor Tipo 2 de Angiotensina/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Adiponectina/sangue , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Temperatura Corporal , Peso Corporal , Tamanho Celular , Ingestão de Energia , Epididimo/anatomia & histologia , Ácidos Graxos/sangue , Insulina/sangue , Masculino , Camundongos Endogâmicos C57BL , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Proteína Desacopladora 1/metabolismo
4.
Exp Eye Res ; 188: 107763, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31421135

RESUMO

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, and individuals with ocular hypertension are at risk to develop POAG. Currently, the only modifiable risk factor for glaucoma progression is lowering of intraocular pressure (IOP). A novel mechanism for lowering IOP involves activation of the type B natriuretic peptide receptor (NPR-B), the naturally occurring agonist of which is C-type natriuretic peptide (CNP). Being a cyclic peptide of 22 amino acids, CNP does not readily penetrate the cornea and its ocular hypotensive effect requires intraocular injection. TAK-639 is a synthetic, cornea-permeable, 9-amino acid CNP analog has been studied for the treatment of ocular hypertension and POAG. We assessed TAK-639 in a receptor binding profile and the effects of TAK-639 on NPR-B-mediated cyclic GMP production in cultured transformed human trabecular meshwork (TM) cells (GTM-3). We also evaluated the effects of topical ocular administration of TAK-639 on mouse IOP and aqueous humor dynamics. Among 89 non-natriuretic peptide receptors, transporters, and channels evaluated, TAK-639 at 10 µM displaced ligand binding by more than 50% to only two receptors: the type 2 angiotensin receptor (IC50 = 8.2 µM) and the cholecystokinin A receptor (IC50 = 25.8 µM). In vitro, TAK-639 selectively activates NPR-B (EC50 = 61 ±â€¯11 nM; GTM-3 cells) relative to NPR-A (EC50 = 2179 ±â€¯670 nM; 293T cells). In vivo, TAK-639 lowered mouse IOP by three mechanisms: increase in aqueous humor outflow facility (C), reduction in the aqueous humor formation rate (Fin), and reduction in episcleral venous pressure (Pe). The maximum mean IOP decreases from baseline were -12.1%, -21.0%, and -36.1% for 0.1%, 0.3%, and 0.6% doses of TAK-639, respectively. Maximum IOP-lowering effect was seen at 2 h, and the duration of action was >6 h. With TAK-639 0.6%, at 2 h post-dose, aqueous outflow facility (C) increased by 155.8%, Fin decreased by 41.0%, the uveoscleral outflow rate (Fu) decreased by 52.6%, and Pe decreased by 31.5% (all p < 0.05). No ocular adverse effects were observed. TAK-639 is an efficacious IOP-lowering agent, with a unique combination of mechanisms of action on both aqueous formation and aqueous outflow facility. Further study of this mechanism of treatment may optimize pharmacologic outcomes and provide disease management in patients with POAG and ocular hypertension.


Assuntos
Humor Aquoso/fisiologia , Pressão Intraocular/efeitos dos fármacos , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/farmacologia , Malha Trabecular/efeitos dos fármacos , Administração Oftálmica , Animais , Linhagem Celular Transformada , GMP Cíclico/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Soluções Oftálmicas , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor de Colecistocinina A/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Tonometria Ocular , Malha Trabecular/metabolismo
5.
Exp Eye Res ; 187: 107770, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449794

RESUMO

The renin-angiotensin system (RAS) plays a vital role in cardiovascular physiology and body homeostasis. In addition to circulating RAS, a local RAS exists in the retina. Dysfunction of local RAS, resulting in increased levels of Angiotensin II (Ang II) and activation of AT1R-mediated signaling pathways, contributes to tissue pathophysiology and end-organ damage. Activation of AT2R on other hand is known to counteract the effects of AT1R activation and produce anti-inflammatory and anti-oxidative effects. We examined the expression of angiotensin receptors in the retina by using transgenic dual reporter mice and by real-time RT-PCR. We further evaluated the effects of C21, a selective agonist of AT2R, in reducing Ang II, lipopolysaccharide (LPS) and hydrogen peroxide induced oxidative stress and inflammatory responses in cultured human ARPE-19 cells. We showed that both AT1Ra and AT2R positive cells are detected in different cell types of the eye, including the RPE/choroid complex, ciliary body/iris, and neural retina. AT1Ra is more abundantly expressed than AT2R in mouse retina, consistent with previous reports. In the neural retina, AT1Ra are also detected in photoreceptors whereas AT2R are mostly expressed in the inner retinal neurons and RGCs. In cultured human RPE cells, activation of AT2R with C21 significantly blocked Ang II, LPS and hydrogen peroxide -induced NF-κB activation and inflammatory cytokine expression; Ang II and hydrogen peroxide-induced reactive oxygen species (ROS) production and MG132-induced apoptosis, comparable to the effects of Angiotensin-(1-7) (Ang-(1-7)), another protective component of the RAS, although C21 is more potent in reducing some of the effects induced by Ang II, whereas Ang-(1-7) is more effective in reducing some of the LPS and hydrogen peroxide-induced effects. These results suggest that activation of AT2R may represent a new therapeutic approach for retinal diseases.


Assuntos
Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Angiotensina/agonistas , Epitélio Pigmentado da Retina/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia
6.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
7.
Int J Med Sci ; 16(6): 813-821, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337954

RESUMO

Background and Objective: Colorectal cancer (CRC) is a major health problem in developed countries. Adenomatous lesions in the large bowel are the main precursors of CRC and the adenoma-adenocarcinoma sequence still provides a solid model for research on carcinogenesis. The finding of local renin-angiotensin systems (RAS) has been crucial to understand the role of this peptidergic system in cancer and has opened new perspectives in the study of colorectal carcinogenetic processes. Methods: In this study we analyzed the immunohistochemical expression of three main RAS receptors (AT1, AT2 and MAS) in a large series of CRC samples (n=161), including uninvolved intestinal mucosa-adenoma-adenocarcinoma sequences from the same patients (n=50). Results: 1) AT1 and AT2 showed a biphasic expression pattern along the sequence. The expression significantly decreased in adenomas with respect to uninvolved mucosa but increased in CRCs. 2) AT2 expression was lower in advanced CRCs with high local invasion (pT4), high stage (IV), high nodal (N2) and vascular invasion. 3) MAS receptor was moderately expressed in the uninvolved mucosa and in adenomas. This expression increased very significantly in CRC tissues. Conclusions: These results suggest that: 1) RAS receptors are differentially regulated as the genetic and epigenetic alterations accumulate throughout the uninvolved mucosa-adenoma-CRC sequence. 2) Loss of AT2 expression could contribute to the aggressive behavior of advanced CRC cells.


Assuntos
Adenocarcinoma/genética , Adenoma/genética , Biomarcadores Tumorais/genética , Carcinogênese/genética , Neoplasias Colorretais/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/mortalidade , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Epigênese Genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/genética
8.
Plast Reconstr Surg ; 144(2): 372-384, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348346

RESUMO

BACKGROUND: We investigated expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 by the embryonic stem cell-like population on the endothelium of the microvessels and perivascular cells within keloid-associated lymphoid tissues. METHODS: Immunohistochemical staining for prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 was performed on 11 formalin-fixed, paraffin-embedded sections of keloid tissue samples. Immunofluorescence staining was performed on three keloid tissue samples by co-staining with OCT4, CD34, ERG, and tryptase. Real-time quantitative polymerase chain reaction was performed on five keloid tissue samples and four keloid-derived primary cell lines. Western blotting was performed on the four keloid-derived primary cell lines for mRNA and protein expression of these proteins, respectively. RESULTS: Immunohistochemical and immunofluorescence staining showed expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 in all 11 keloid tissue samples. Prorenin receptor and angiotensin II receptor 1 were expressed on the endothelium and the pericyte layer of the microvessels and perivascular cells, angiotensin II receptor 2 was localized to the endothelium of the microvessels and the tryptase-positive perivascular cells, and angiotensin-converting enzyme was localized to the endothelium of the microvessel, within the keloid-associated lymphoid tissues. Real-time quantitative polymerase chain reaction showed transcripts of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid tissue samples and keloid-derived primary cell lines, whereas angiotensin II receptor 2 was detected in keloid tissue samples only. Western blotting confirmed the presence of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid-derived primary cell lines. CONCLUSION: Prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 were expressed by the embryonic stem cell-like population within the keloid-associated lymphoid tissues, suggesting that this primitive population may be a potential therapeutic target by modulation of the renin-angiotensin system.


Assuntos
Células-Tronco Embrionárias/metabolismo , Queloide/metabolismo , Sistema Renina-Angiotensina/fisiologia , Adolescente , Adulto , Antígenos CD34/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Feminino , Imunofluorescência , Humanos , Queloide/patologia , Masculino , Pessoa de Meia-Idade , Fator 3 de Transcrição de Octâmero/metabolismo , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Superfície Celular/metabolismo , Regulador Transcricional ERG/metabolismo , Adulto Jovem
9.
Biomed Pharmacother ; 116: 108954, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108352

RESUMO

BACKGROUND: This study tested the hypothesis that Entresto could safely and effectively preserve heart and kidney function in rats with cardiorenal syndrome (CRS) induced by 5/6 nephrectomy and intra-peritoneal doxorubicin administration (accumulated dosage up to 7.5 mg/kg) together with daily high-protein-diet (HPD). METHODS AND RESULTS: Adult male Sprague-Dawley rats (n = 24) were equally categorized into Group 1 (sham-operated control + HPD), Group 2 (CRS + HPD) and Group 3 [CRS + HPD + Entresto (100 mg/kg/day orally) since Day 14 after CRS induction] and euthanized by Day 63 after CRS induction. By Day 63, circulatory BUN and creatinine levels and ratios of urine protein to creatinine were significantly higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, whereas left-ventricular ejection fraction and kidney weight showed an opposite pattern among all groups (all p < 0.001). Microscopically, fibrosis area and intensity of oxidative stress (i.e., DCFDA stain) in kidney/heart tissues exhibited a pattern identical to that of creatinine level among all groups (all p < 0.0001). Kidney injury score and protein expressions of autophagy (i.e., beclin-1/Atg-5/protein ratio of LC3-BII/LC3-BI), fibrosis (Smad3/TGF-ß), apoptosis (mitochondrial-Bax/capase2/3/9), oxidative-stress (NOX-4/oxidized protein/xanthine-oxidase/catalase), membranous p47phox phosphorylation and mitochondrial-damage biomarker (cytosolic-cytochrome-C) were higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, while protein expressions of anti-apoptosis (Bcl-2/Bcl-XL) and mitochondrial integrity (mitochondrial-cytochrome-C) markers displayed an opposite pattern among all groups in kidney tissues (all p < 0.0001). CONCLUSION: Oral administration of entresto was safe and could offer protection against CRS-induced heart and kidney damage.


Assuntos
Aminobutiratos/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Dieta Rica em Proteínas , Rim/patologia , Tetrazóis/uso terapêutico , Aminobutiratos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Nitrogênio da Ureia Sanguínea , Síndrome Cardiorrenal/sangue , Síndrome Cardiorrenal/genética , Síndrome Cardiorrenal/fisiopatologia , Creatinina/sangue , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miocárdio/patologia , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Tetrazóis/farmacologia
10.
Anesth Analg ; 128(6): e84-e87, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31094778

RESUMO

Recent findings from a phase II clinical trial showed analgesic effects of an angiotensin II type-2 receptor (AT2R) antagonist in postherpetic neuralgia patients. This study aimed to investigate whether AT2R antagonism could provide effective analgesia in voluntary measures of unevoked/ongoing pain-like behaviors in mice with experimental neuropathy. Mice were subjected to spared nerve injury to induce neuropathy and tested in 2 operant behavioral tests to measure ongoing mechanical and cold pain hypersensitivities. Systemic administration of an AT2R antagonist provided effective analgesia in these behavioral measures of mechanical and cold pain in spared nerve injury mice, suggesting its effectiveness in neuropathic pain.


Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II/administração & dosagem , Temperatura Baixa , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Analgesia , Angiotensina II/metabolismo , Animais , Comportamento Animal , Feminino , Marcha , Imidazóis/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Manejo da Dor , Piridinas/administração & dosagem , Receptor Tipo 2 de Angiotensina/metabolismo
11.
Hypertension ; 73(6): 1258-1265, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31030607

RESUMO

Activation of the renal D1R (dopamine D1-like receptor) or AT2R (angiotensin II type-2 receptor), individually or both, simultaneously, is necessary in the normal regulation of renal sodium (Na+) transport and blood pressure. However, little is known regarding the precise mechanism of this interaction. Pharmacological stimulation, membrane biotinylation, and cell surface immunofluorescence were used to study the effect of the D1R/AT2R interaction in human renal proximal tubule cells. D1R activation of GαS stimulates AC (adenylyl cyclase) and induces apical plasma membrane recruitment of AT2Rs. We now show for the first time the reciprocal reaction, AT2R stimulation with Ang III (angiotensin III) leads to the apical plasma membrane recruitment of the D1R. The cell-permeable second messenger analogs of cAMP (8-Br-cAMP) or cGMP (8-Br-cGMP) induce translocation of both D1R and AT2R to the plasma membrane. Inhibition of PKA (protein kinase A) with Rp-cAMPS and PKG (protein kinase G) with Rp-8-CPT-cGMPS blocks D1R and AT2R recruitment, respectively, indicating that both PKA and PKG are necessary for D1R and AT2R trafficking. Both 8-Br-cAMP and 8-Br-cGMP activate PP2A (protein phosphatase 2A), which is necessary for both plasma membrane recruitment of D1R and AT2R and the inhibition of sodium hydrogen exchanger 3-dependent Na+ transport. These studies provide insights into the D1R/AT2R transregulation mechanisms that play a crucial role in maintaining Na+ and ultimately blood pressure homeostasis.


Assuntos
Pressão Sanguínea/fisiologia , Túbulos Renais Proximais/metabolismo , Proteína Fosfatase 2/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Dopamina D1/metabolismo , Sódio/metabolismo , Western Blotting , Membrana Celular/metabolismo , Células Cultivadas , Humanos , Transporte de Íons , Túbulos Renais Proximais/citologia , Natriurese , Transdução de Sinais
12.
Biomed Pharmacother ; 114: 108660, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974387

RESUMO

Dendritic cells (DCs) play a complex role in the progression of myocardial infarction (MI). The impact of angiotensin-converting enzyme (ACE) inhibitor therapy, partly via affecting DCs maturation and recruitment, was tested on a MI mouse model. Furthermore, the cardioprotective effects of ACEI were enhanced through attenuating migration of DCs from the spleen into peripheral circulation, thereby inhibiting DCs maturation and tissue inflammation. ACEI repress DCs immune inflammatory response through down-regulating DCs maturation surface markers and regulating inflammatory cytokines, which led to a higher survival rate, improved function and remodeling through decreased inflammatory response after MI. However, inhibition of AT2R activation, resulted in a reduction of ACEI effects on DCs. The potent anti-inflammatory effect of ACEI can partially be attributed to its impact on DCs through activation of AT2R, which may provide a new target mechanism for ACEI therapy after MI.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Dendríticas/efeitos dos fármacos , Coração/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Receptor Tipo 2 de Angiotensina/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Taxa de Sobrevida
13.
Clin Sci (Lond) ; 133(8): 971-982, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30988133

RESUMO

The renin-angiotensin system (RAS) is present in the gastrointestinal (GI) tract but remains to be fully characterized, particularly in man. The duodenum plays a role in both the upper and lower GI regulation, as well as in distant organs. The present study investigates the presence and functional potential of RAS in the human duodenal mucosa of healthy individuals. Endoscopically acquired mucosal biopsies from healthy volunteers were examined using western blot, immunohistochemistry, and ELISA. Functionality was examined by using Ussing chambers and recording duodenal transmucosal potential difference (PD) and motility in vivo Angiotensinogen, Angiotensin II (AngII) and its receptors (AT1R, AT2R) as well as to the RAS associated enzymes renin, ACE, and neprylisin were detected in all samples of duodenal mucosa. Migrating motility complex induced elevations of transmucosal PD were significantly larger after per-oral administration of the AT1R receptor antagonist candesartan. Fasting duodenal motility per se was not influenced by candesartan. The epithelial current produced by duodenal mucosae mounted in Ussing chambers increased significantly after addition of AngII to specimens where the AT1R was blocked using losartan. The epithelial current also increased after addition of the AT2R-selective agonist C21. Immunostaining and pharmacological data demonstrate the presence of a local RAS in the human duodenal mucosa with capacity to influence epithelial ion transport by way of particulary the AT2R.


Assuntos
Duodeno/metabolismo , Mucosa Intestinal/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Renina/metabolismo , Adulto , Angiotensina II/genética , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Benzimidazóis/administração & dosagem , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Losartan/administração & dosagem , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Renina/genética , Sistema Renina-Angiotensina , Tetrazóis/administração & dosagem , Adulto Jovem
14.
J Endocrinol ; 241(3): 235-247, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978701

RESUMO

During circulatory shock, gastrointestinal microcirculation is impaired, especially via activation of the renin-angiotensin-aldosterone system. Therefore, inhibition of the renin-angiotensin-aldosterone system might be beneficial in maintaining splanchnic microcirculation. The aim of this study was to analyze whether locally applied losartan influences gastric mucosal perfusion (µflow, µvelo) and oxygenation (µHbO2) without systemic hemodynamic changes. In repetitive experiments six anesthetized dogs received 30 mg losartan topically on the oral and gastric mucosa during normovolemia and hemorrhage (-20% blood volume). Microcirculatory variables were measured with reflectance spectrometry, laser Doppler flowmetry and incident dark field imaging. Transpulmonary thermodilution and pulse contour analysis were used to measure systemic hemodynamic variables. Gastric barrier function was assessed via differential absorption of inert sugars. During normovolemia, losartan increased gastric µflow from 99 ± 6 aU to 147 ± 17 aU and µvelo from 17 ± 1 aU to 19 ± 1 aU. During hemorrhage, losartan did not improve µflow. µvelo decreased from 17 ± 1 aU to 14 ± 1 aU in the control group. Application of losartan did not significantly alter µvelo (16 ± 1 aU) compared to the control group and to baseline levels (17 ± 1 aU). No effects of topical losartan on macrohemodynamic variables or microcirculatory oxygenation were detected. Gastric microcirculatory perfusion is at least partly regulated by local angiotensin receptors. Topical application of losartan improves local perfusion via vasodilation without significant effects on systemic hemodynamics. During mild hemorrhage losartan had minor effects on regional perfusion, probably because of a pronounced upstream vasoconstriction.


Assuntos
Microcirculação , Perfusão , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/metabolismo , Animais , Cães , Feminino , Mucosa Gástrica/metabolismo , Hemodinâmica , Hemorragia , Intestinos , Fluxometria por Laser-Doppler , Losartan/farmacologia , Microscopia de Vídeo , Oxigênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Choque , Choque Hemorrágico/metabolismo , Circulação Esplâncnica , Estômago , Termodiluição
15.
Can J Physiol Pharmacol ; 97(6): 581-588, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30730762

RESUMO

Endocardial endothelial cells (EECs) form a monolayer lining the ventricular cavities. Studies from our laboratory and the literature have shown differences between EECs isolated from the right and left ventricles (EECRs and EECLs, respectively). Angiotensin II (Ang II) was shown to induce apoptosis of different cell types mainly via AT1 receptor activation. In this study, we verified whether Ang II induces apoptosis of human EECRs and EECLs (hEECRs and hEECLs, respectively) and via which type of receptor. Using the annexin V labeling and in situ TUNEL assays, our results showed that Ang II induced apoptosis of both hEECRs and hEECLs in a concentration-dependent manner. Our results using specific AT1 and AT2 receptor antagonists showed that the Ang-II-induced apoptosis in both hEECRs and hEECLs is mediated mainly via the AT2 receptor. However, AT1 receptor blockade partially prevented Ang-II-induced apoptosis, particularly in hEECRs. Hence, our results suggest that mainly AT2 receptors mediate Ang-II-induced apoptosis of hEECRs and hEECLs. The damage of EECs would affect their function as a physical barrier between the blood and cardiomyocytes, thus affecting cardiomyocyte functions.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Ventrículos do Coração/citologia , Receptor Tipo 2 de Angiotensina/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Humanos , Fatores de Tempo
16.
Pancreas ; 48(2): 250-256, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30629032

RESUMO

OBJECTIVE: We aim to investigate whether C21, a selective angiotensin type 2 receptor agonist, can exert protective effects on pancreatic ß-cells through activation of antiapoptosis and autophagy. METHODS: The high-fat diet-induced obese rats (HFDs) were under C21 treatment for 4 weeks. RESULTS: C21 treatment decreased the fasting glucose levels and improved ß-cell insulin secretory function in the HFD group. Hematoxylin and eosin staining and electron microscopy indicated that the islet morphology was improved in the C21-treated obese rats, which was associated with increased levels of the key transcription factor PDX1, glucose sensing, and uptaking protein GCK and GLUT2, respectively. C21 treatment exerted antiapoptotic effects through decreasing the levels of apoptotic marker Caspase-3 while increasing the levels of antiapoptotic markers AKT, p-AKT, and BCL2. C21 treatment also induced autophagosome formation in the mitochondria of the ß-cells in the HFD group accompanied by increased levels of autophagy markers, LC-3B and Beclin-1. CONCLUSIONS: The results suggested C21 treatment decreased the fasting glucose level and protected ß-cell function in the HFD-induced obese rat model, which in part through activation of antiapoptotic and autophagy processes. This study provided preclinical evidence for the utilization of C21 in the treatment of type 2 diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/agonistas , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Masculino , Microscopia Eletrônica , Obesidade/etiologia , Obesidade/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/ultraestrutura , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/metabolismo
17.
Nitric Oxide ; 84: 50-59, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611765

RESUMO

The perivascular adipose tissue (PVAT) is located around the adventitia, composed primarily by adipocytes, stromal cells, leukocytes, fibroblasts and capillaries. It is well described that PVAT is an important modulator of the vascular tone being considered a biologically active tissue, releasing both vasoconstrictor and vasodilators factors. The literature shows that the anti-contractile effect induced by PVAT may be due to activation of the renin-angiotensin system (RAS). AIM: Investigate whether the renin-angiotensin system participates in the effect exerted by perivascular adipose tissue on the vascular tone. METHODS AND RESULTS: For this study we used thoracic aorta from Balb/c mice and performed vascular reactivity, nitric oxide and hydrogen peroxide quantification using selective probes and fluorescence microscopy, immunofluorescence to locate receptors and enzymes involved in this response. Our results demonstrated that perivascular adipose tissue induces an anti-contractile effect in endothelium-independent manner and involves Mas and AT2 receptors participation with subsequent PI3K/Akt pathway activation. This pathway culminated with nitric oxide and hydrogen peroxide production by neuronal nitric oxide synthase, being hydrogen peroxide most relevant for the anti-contractile effect of perivascular adipose tissue. CONCLUSION: For the first time in the literature, our results show the presence of Mas and AT2 receptors, as well as, nitric oxide synthase on perivascular adipose tissue. Furthermore, our results show the involvement of Mas and AT2 receptors and consequently nitric oxide synthase activation in the anti-contractile effect exerted by perivascular adipose tissue.


Assuntos
Tecido Adiposo/metabolismo , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/fisiologia , Vasoconstrição/fisiologia , Túnica Adventícia/anatomia & histologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Aorta Torácica/metabolismo , Endotélio Vascular/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Fenilefrina/farmacologia , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/metabolismo
18.
Nutr Metab Cardiovasc Dis ; 29(3): 301-305, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30642787

RESUMO

BACKGROUND AND AIMS: Although many studies have reported the effects of AT1 receptor on dietary salt overload, the role of AT2 receptor in this model is far from completely elucidated. The present study aimed to better understand the role of AT2 receptor in cardiac structure alterations in response to chronic high salt intake in rats. METHODS AND RESULTS: Male Wistar rats were fed a normal or high salt diet from weaning until 18 weeks of age. Both groups were subdivided into two groups. Starting at 7 weeks of age, rats were treated with or without compound 21 (0.3 mg/kg/day, n = 16), an AT2 receptor agonist. Metabolics and structural parameters were measured. BP, transverse cardiomyocyte and intersticial fibrose was higher in animals fed with high salt diet compared with normal salt fed animals. CONCLUSION: Compound 21 prevented the development of cardiac hypertrophy and fibrosis, reduced the increase in blood pressure and prevented the lower weight gain in animals fed a high salt diet.


Assuntos
Cardiomegalia/prevenção & controle , Fármacos Cardiovasculares/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/agonistas , Cloreto de Sódio na Dieta , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Fibrose , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
19.
Mol Neurobiol ; 56(4): 3005-3023, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30076526

RESUMO

Microglia-induced reactive oxygen species (ROS) production and inflammation play an imperative role in neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). It has been established that angiotensin II type-2 receptor (AT2R) activation is neuroprotective in central nervous system diseases like stroke and AD. However, the involvement of AT2R in NADPH oxidase (NOX)-mediated microglia activation is still elusive. Therefore, the present study investigated the role of AT2R in angiotensin II (Ang II) or Phorbol 12-myristate 13-acetate (PMA)-induced microglia activation in BV2 cells, primary microglia, p47phox knockout (p47KO) microglia, and in vivo. Treatment of microglia with Ang II or PMA induced a significant ROS generation and promoted pro-inflammatory microglia in a NOX-dependent manner. In contrast, AT2R activation by CGP42112A (CGP) inhibited NOX activation, ROS production, and pro-inflammatory microglia activation, while promoting the immunoregulatory microglia. This inhibitory effect of AT2R on NOX and pro-inflammatory activation was attenuated by AT2R antagonist, PD123319. Essentially, NOX inhibition (by DPI) or scavenging cellular ROS (by NAC) or p47KO microglia were immune to Ang II- or PMA-induced pro-inflammatory microglia activation. Mechanistically, AT2R, via activation of protein phosphatase-2A (PP2A), prevented the Ang II- or PMA-induced protein kinase C (PKC) activation and phosphorylation of p47phox, an effect that was reversed by the addition of PP2A inhibitor, Okadaic acid (OA). Importantly, PKC inhibitor, Rottlerin, inhibited the Ang II- or PMA-induced p47phox phosphorylation and ROS generation to the similar extent as AT2R activation. In addition, AT2R activation or p47KO prevented ROS production, pro-inflammatory microglial activation, and sickness behavior in mice model of neuroinflammation. Therefore, the present findings suggested that AT2R, via PP2A-mediated inhibition of PKC, prevents the NOX activation, ROS generation, and subsequent pro-inflammatory activation of microglia.


Assuntos
Inflamação/patologia , Microglia/metabolismo , Microglia/patologia , NADPH Oxidases/metabolismo , Proteína Quinase C/metabolismo , Proteína Fosfatase 2/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Angiotensina II , Animais , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Lipopolissacarídeos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetato de Tetradecanoilforbol/farmacologia
20.
Kidney Int ; 95(1): 138-148, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30442332

RESUMO

Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-γ, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-γ antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.


Assuntos
Doenças da Aorta/tratamento farmacológico , Fosfatos/toxicidade , Receptor Tipo 2 de Angiotensina/metabolismo , Calcificação Vascular/tratamento farmacológico , Adenina/toxicidade , Animais , Aorta Torácica/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Fosfatos/sangue , Cultura Primária de Células , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/genética , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Calcificação Vascular/patologia
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