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1.
Life Sci ; 240: 117085, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759042

RESUMO

AIMS: Our study was designed to explore the function and mechanism of Tanshinone IIA in alleviating pain syndrome caused by endometriosis (EMs). MAIN METHODS: Female Sprague-Dawley rats went through autotransplantation operation to establish EMs model. The rats were randomly divided into five groups: sham, model, positive, Tanshinone IIA (L) (3 mg/kg/d) and Tanshinone IIA (H) (12 mg/kg/d) group. Volume of ectopic endometrium was measured after 21 days of continuous administration. Serum estradiol (E2) was detected by enzyme linked immunosorbent assay (Elisa). The protein expression of angiotensinogen (AGT), renin (REN), angiotensin converting enzyme (ACE), angiotensin II (ANGII) and angiotensin II type 2 receptor (AT2) in the dorsal root ganglion (DRG) neurons were measured by immunohistochemistry and Western Blotting. The mRNA expression levels of AGT and ANGII were measured by Real-time polymerase chain reaction (PCR). KEY FINDINGS: Tissue measurements showed that tanshinone IIA significantly inhibited the growth of ectopic endometrium. Tanshinone IIA could improve the paw withdrawal threshold thus reducing the mechanical hyperalgesia of EMs rats. Moreover, Tanshinone IIA regulated the DRG renin angiotensin system (RAS) by reducing the protein expression of AGT, REN, ACE, ANGII and AT2 in DRG neurons. Furthermore, Real-time PCR results also showed that the mRNA expression levels of AGT and ANGII in the DRG neurons were decreased. SIGNIFICANCE: The Tanshinone IIA inhibitory effect on the EMs associated pain in EMs rats might occur through decreasing the expression of E2, ANGII and AT2, thus halting DRG sprouting and promoting hyperalgesia threshold.


Assuntos
/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Axônios/patologia , Endometriose/tratamento farmacológico , Gânglios Espinais/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Endometriose/patologia , Estradiol/metabolismo , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Ratos , Ratos Sprague-Dawley
2.
Int J Mol Sci ; 20(19)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31623362

RESUMO

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis.


Assuntos
Angiotensina II/metabolismo , Transdiferenciação Celular , Miofibroblastos/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Transdução de Sinais , Angiotensina II/farmacologia , Sinalização do Cálcio , Sobrevivência Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Humanos , Hipertrofia , Imagem Molecular , Mioblastos/citologia , Mioblastos/metabolismo , Miofibroblastos/citologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
3.
Biomed Res Int ; 2019: 1806234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531346

RESUMO

We previously demonstrated that angiotensin-(1-7) (Ang-(1-7)), an essential endocrine factor, inhibits the NLRP3 inflammasome by regulating reactive oxygen species (ROS) in fibrotic livers. We also demonstrated that the NLRP3 inflammasome contributes to the liver damage induced by pyroptosis after heatstroke. However, the role of Ang-(1-7) in the hepatocytes under heat stress remains uncertain. We aimed to examine the change in angiotensin peptides in the livers affected by heatstroke and the effect on the ROS-NLRP3 inflammatory signalling pathway. In vivo, increased angiotensin II (Ang II) and decreased Ang-(1-7) in the serum of heatstroke patients suffering from hepatic dysfunction were observed. The change in angiotensin peptides was considered a potential biomarker that could be used to predict hepatic dysfunction. Enhanced Ang II and attenuated Ang-(1-7) levels were also observed in the liver tissue of heatstroke rats, which were consistent with their receptors and converting enzymes. Hepatic damage associated with increased ROS and protein expression levels of NOX4, NLRP3, caspase-1, and IL-1ß was attenuated by AVE 0991, an analogue of Ang-(1-7). In vitro, pyroptosis, characterized by activated caspase-1 and IL-1ß, was observed in hepatocytes under heat stress, which was enhanced by Ang II and attenuated by antioxidants, NOX4 siRNA, and AVE 0991. In summary, AVE 0991 attenuates pyroptosis and liver damage induced by heat stress by inhibiting the ROS-NLRP3 inflammatory signalling pathway.


Assuntos
Golpe de Calor/tratamento farmacológico , Imidazóis/farmacologia , Inflamação/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Biomarcadores/metabolismo , Golpe de Calor/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Fígado , Cirrose Hepática/metabolismo , Masculino , Fragmentos de Peptídeos/metabolismo , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Pak J Pharm Sci ; 32(3 Special): 1355-1359, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551215

RESUMO

Mitogen-activated protein kinase (MAPK) cascades are important players in the cellular signal pathways, and the deregulation of MAPKs is involved in a variety of diseases, especially cardiovascular disorders. This study was designed to investigate the effects of quercetin on proliferation of cardiac fibroblasts, measured the secretion of Col I & Col III by ELISA and the expression of extra cellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) p38 by eastern blotting in cardiac fibroblasts challenged with angiotensin (Ang-II). Results showed that Ang-II significantly increased the DNA synthesis and collagen secretion. In contrast, quercetin reversed such effects and inhibited cardiac fibroblasts proliferation. Furthermore, reactive oxygen species (ROS) stimulated the phosphorylation of ERK, p38 and JNK, while pre-administration of quercetin significantly (P<0.05) reduced the phosphorylation. All these evidences revealed that quercetin inhibited the MAPK pathway activation via ROS.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miocárdio/patologia , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Cardiotônicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Coração/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Miocárdio/metabolismo , Ratos Wistar
5.
Mol Med Rep ; 20(3): 2796-2804, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524252

RESUMO

The renin­angiotensin system (RAS) serves an essential role in hypertension. MicroRNAs (miRs) have been reported to be important regulators in angiotensin (Ang) II­dependent hypertension. We aimed to explore the roles of Ang II and miR­133a in the mechanism underlying hypertension. Human umbilical vein endothelial cells (HUVECs) were identified by immunofluorescence staining. Cell viability and miR­133a expression under the inhibition of Ang II of various concentrations were determined by an MTT assay and reverse transcription­quantitative polymerase chain reaction (RT­qPCR), respectively. The effects of HUVECs transfected with miR­133a mimic or inhibitor on Ang II­induced apoptosis were measured using flow cytometry. The potential targeting of miR­133a to the 3' untranslated region of (pro) renin receptor (PRR) was assessed using TargetScan and a dual­luciferase assay. The effects of PRR interference using small interfering (si)RNA on PRR expression and the rate of apoptosis were determined by RT­qPCR, western blotting and flow cytometry, respectively. Ang II at a concentration of 10­5 M significantly inhibited the cell viability (P<0.05) and miR­133a expression (P<0.01); Downregulation of miR­133a suppressed cell viability. HUVECs transfected with miR­133a mimic reduced the rate of Ang II­induced apoptosis from 21.99 to 12.38%, but miR­133a inhibitor promoted Ang II­induced apoptosis (apoptosis rate, 28.9%). PRR was predicted to be a target gene of miR­133a. Transfection with siPRR decreased the apoptotic rate in Ang II + negative control and Ang II + miR­133a inhibitor group to 11.39 and 12.94%, respectively. Our findings also suggested that Ang II promoted PRR expression to enhance the apoptotic rate of HUVECs via the suppression of miR­133a. Furthermore, siPRR efficiently decreased the Ang II­induced apoptosis.


Assuntos
Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/genética , Interferência de RNA , Regiões 3' não Traduzidas , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Biomarcadores , Sobrevivência Celular/efeitos dos fármacos , Imunofluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina , ATPases Vacuolares Próton-Translocadoras/metabolismo
6.
J Sci Food Agric ; 99(15): 6822-6832, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31385307

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitory peptides were found to alleviate acute hepatitis significantly. In this study, we purified and identified ACE inhibitory peptide from cashew to evaluate its protective role on alcohol-induced acute hepatitis in mice. RESULTS: The ACE inhibitory peptides were purified by using consecutive chromatographic techniques. One of these peptides (FETISFK) exhibited the highest ACE inhibition rate (91.04 ± 0.31%). In vivo, the results showed that ACE inhibitory peptide decreased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by alcohol exposure. Moreover, it could increase the activities of superoxide dismutase (SOD) and glutathione (GSH), and decrease the level of malondialdehyde (MDA). It was also found to down-regulate markedly the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). It could also decrease the expression of ACE, angiotensin II (AngII) and angiotensin II type 1 receptor (AT1 R). CONCLUSION: These findings support the view that the ACE inhibitory peptide alleviated acute hepatitis by down-regulating the ACE-AngII-AT1 R axis, broadening the research approach to prevent acute hepatitis, and providing experimental data for the development and utilization of cashews. © 2019 Society of Chemical Industry.


Assuntos
Anacardium/química , Inibidores da Enzima Conversora de Angiotensina/química , Hepatite/tratamento farmacológico , Peptídeos/química , Extratos Vegetais/química , Doença Aguda/terapia , Álcoois/efeitos adversos , Angiotensina II/genética , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Hepatite/enzimologia , Hepatite/etiologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Nozes/química , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Redox Biol ; 26: 101295, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31421410

RESUMO

Hypertension is one of the major predisposing factors for neurodegenerative disease characterized with activated renin-angiotensin system (RAS) in both periphery and brain. Vitamin D (VitD) is recently recognized as a pleiotropic hormone with strong neuroprotective properties. While multiple lines of evidence suggest that VitD can act on RAS, the evidence concerning the crosstalk between VitD and RAS in the brain is limited. Therefore, this study aims to evaluate whether VitD can modulate brain RAS to trigger neuroprotective actions in the brain of spontaneously hypertensive rats (SHR). Our data showed that calcitriol treatment induced VDR expression and inhibited neural death in the prefrontal cortex of SHR. Sustained calcitriol administration also inhibited microglia M1 polarization, but enhanced M2 polarization, accompanied with decreased expression of proinflammatory cytokines. We then further explored the potential mechanisms and showed that SHR exhibited overactivated classical RAS with increased expression of angiotensin II (Ang II) receptor type 1 (AT1), angiotensin converting enzyme (ACE) and Ang II production, whereas the counteracting arm of traditional RAS, ACE2/Ang(1-7)/MasR, was impaired in the SHR brain. Calcitriol nonsignificantly suppressed AT1 and ACE but markedly reduced Ang II formation. Intriguingly, calcitriol exerted pronouncedly impact on ACE2/Ang(1-7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1-7) generation. Meanwhile, calcitriol ameliorated the overactivation of NADPH-oxidase (Nox), the downstream of RAS, in SHR, and also mitigated oxidative stress. In microglial (BV2) cells, we further found that calcitriol induced ACE2 and MasR with no significant impact on ACE and AT1. In accordance, calcitriol also attenuated Ang II-induced Nox activation and ROS production, and shifted the microglia polarization from M1 to M2 phenotype. However, co-treatment with A779, a specific MasR antagonist, abrogated the antioxidant and neuroimmune modulating actions of VitD. These findings strongly indicate the involvement of ACE2/Ang(1-7)/MasR pathway in the neuroprotective mechanisms of VitD in the hypertensive brain.


Assuntos
Angiotensina II/metabolismo , Microglia/metabolismo , Estresse Oxidativo , Receptores de Calcitriol/metabolismo , Angiotensina II/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Cultivadas , Suscetibilidade a Doenças , Masculino , Camundongos , Microglia/efeitos dos fármacos , NADPH Oxidases/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Endogâmicos SHR , Receptores de Calcitriol/agonistas , Sistema Renina-Angiotensina , Transdução de Sinais , Vitamina D/farmacologia
8.
Life Sci ; 234: 116792, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465733

RESUMO

AIMS: Assisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. MATERIALS AND METHODS: Human umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. KEY FINDINGS: In IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SIGNIFICANCE: The hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.


Assuntos
Angiotensina II/metabolismo , Metilação de DNA , Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Receptor Tipo 1 de Angiotensina/genética , Cordão Umbilical/irrigação sanguínea , Vasoconstrição , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Transferência Embrionária/efeitos adversos , Feminino , Fertilização In Vitro/efeitos adversos , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Gravidez , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
9.
Phytother Res ; 33(9): 2440-2447, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31318113

RESUMO

Cardiac fibrosis plays a crucial role in the pathogenesis of myocardial infarction (MI). It has been found that differentiation of cardiac fibroblasts (CFs) into myofibroblasts is a major event in the process of cardiac fibrosis. In the present study, we aimed to investigate the effects of protocatechuic acid (PCA), a cardiac protective agent, on the CFs differentiation in vitro. The results showed that PCA exhibited inhibitory effects on the cell proliferation and migration in angiotensin II (Ang II)-induced CFs. PCA treatment suppressed the Ang II-induced expression of α-smooth muscle actin (α-SMA), which is a hallmark of myofibroblasts. In addition, the production of extracellular matrix (ECM) proteins, including type I collagen (Col I) and connective tissue growth factor (CTGF), were significantly decreased in the PCA-treated CFs. The Ang II-induced increased levels of matrix metalloproteinase (MMP)-2, and MMP-9 were reduced by PCA. Furthermore, PCA resulted in decrease in reactive oxygen species (ROS) generation, as well as the expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme 4 (NOX4) and p-p38 in Ang II-induced CFs. These findings showed that PCA treatment prevented the Ang II-induced cardiac fibrosis by inhibiting the NOX4/ROS/p38 signaling pathway in vitro, suggesting that PCA might be a therapeutic agent for MI.


Assuntos
Angiotensina II/metabolismo , Fibrose/tratamento farmacológico , Hidroxibenzoatos/uso terapêutico , Infarto do Miocárdio/patologia , Miofibroblastos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Hidroxibenzoatos/farmacologia , Transdução de Sinais/efeitos dos fármacos
10.
Int J Mol Sci ; 20(14)2019 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-31330886

RESUMO

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the 'classic' view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.


Assuntos
Transição Epitelial-Mesenquimal , Hipertensão Renal/etiologia , Hipertensão Renal/patologia , Nefrite/etiologia , Nefrite/patologia , Angiotensina II/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Endotelinas/metabolismo , Fibrose , Humanos , Hipertensão/complicações , Hipertensão Renal/metabolismo , Nefrite/metabolismo
11.
Hypertension ; 74(3): 509-517, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31352823

RESUMO

We have previously shown that podocyte injury increases the glomerular filtration of liver-derived Agt (angiotensinogen) and the generation of intrarenal Ang II (angiotensin II) and that the filtered Agt is reabsorbed by proximal tubules in a manner dependent on megalin. In the present study, we aimed to study the role of megalin in the generation of renal Ang II and sodium handling during nephrotic syndrome. We generated proximal tubule-specific megalin KO (knockout) mice and crossed these animals with NEP25 mice, in which podocyte-specific injury can be induced by injection of the immunotoxin LMB2. Without podocyte injury, renal Agt staining was markedly diminished and urinary Agt increased in KO mice. However, renal Ang II was similar between KO and control mice on average: 117 (95% CI, 101-134) versus 101 (95% CI, 68-133) fmol/g tissue. We next tested the effect of megalin KO on intrarenal Ang II generation with podocyte injury. Control NEP25 mice showed markedly increased renal Agt staining and renal Ang II levels: 450 (336-565) fmol/g tissue. Megalin KO/NEP25 mice showed markedly diminished Agt reabsorption and attenuated renal Ang II: 199 (156-242) fmol/g tissue (P<0.001). Compared with control NEP25 mice, megalin KO/NEP25 mice excreted 5-fold more sodium in the urine. Western blot analysis showed that megalin KO decreased NHE3 and the cleaved α and γ forms of Epithelial Na Channel. These data indicate that Agt reabsorbed by proximal tubules via megalin in nephrotic syndrome is converted to Ang II, which may contribute to sodium retention and edema formation by activating NHE3 and Epithelial Na Channel.


Assuntos
Angiotensina II/metabolismo , Hipernatremia/fisiopatologia , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Animais , Biópsia por Agulha , Edema/etiologia , Edema/fisiopatologia , Hipernatremia/metabolismo , Imuno-Histoquímica , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Knockout , Podócitos/citologia , Podócitos/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Fatores de Risco , Sensibilidade e Especificidade , Sódio/metabolismo , Urinálise
12.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356181

RESUMO

Local renin-angiotensin systems (RAS) are found in many tissues. The main physiological effects of RAS are driven by the balance between two pathways: the angiotensin-converting enzyme I - angiotensin II receptor type 1 (ACE1-AT1R) axis and the angiotensin-converting enzyme 2 - Mas-receptor (ACE2-MAS) axis. The local intestinal RAS functions both as a paracrine regulator and as a regulator of inflammation. The expression of local RAS is known to change with age in many tissues, but age-related changes in the intestinal RAS have not been studied comprehensively. The present study characterized age-related changes in two main pathways of local RAS in the jejunum and colon of young and adult rats, in normotensive and hypertensive strains. The main finding was that 33-week-old rats exhibit an increased ratio of ACE1/ACE2 activities and protein quantity ratios compared to young rats. As the relationship of ACE1 and ACE2 mediated pathways drives the total physiological effects of RAS, the results indicate that the function of intestinal RAS changes with age. It is possible that age-related increase in ACE1-AT1R axis introduces more pro-inflammatory and fibrogenic conditions in the intestine.


Assuntos
Hipertensão/fisiopatologia , Intestinos/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/fisiologia , Hipertensão/metabolismo , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/metabolismo
13.
Biomed Pharmacother ; 117: 109124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228798

RESUMO

AIM: Cardiovascular diseases, such as coronary heart disease and myocardial infarction (MI) are currently considered as the leading causes of death and disability. The aim of the present study is to investigate the effects of Xin-Ji-Er-Kang (XJEK) on kidney injury and renal oxidative stress. In addition, the associated mechanism involved in these processes was examined in an MI model, and particularly focused on the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase-1 (HO-1) pathway. MATERIALS AND METHODS: A total of 138 Sprague-Dawley rats were used in the present study. The control group was designated as 0 wk (n = 8). A total of 3 phases (2, 4, 6 wk) of administration were used in the sham-operated groups (sham, n = 10), MI groups (MI, n = 10), MI + XJEK groups (XJEK, n = 10) and MI + fosinopril groups (fosinopril, n = 10). Additional 10 rats were used to evaluate the infarct area. At 2, 4 or 6 wk post-MI, the hemodynamic parameters were monitored, the rats were sacrificed, then blood, heart and renal tissues were collected for furtherly analysis. RESULTS: The results indicated that XJEK administration continuously ameliorated renal hypertrophy index, blood urea nitrogen and cystatin C concentrations. XJEK further improved post-MI cardiac function by limiting scar formation and caused a downregulation in the hemodynamic parameters at the end of 2 and 4 wk. The hemodynamic parameters were upregulated after 6 wk treatment with XJEKcompared with those noted in the MI groups. Similarly, XJEK treatment for 2 wk potentiated Nrf2 nuclear translocation and HO-1 expression and inhibited the deficiency of nuclear Nrf2 and HO-1 at 6 wk post-MI compared with that of the MI groups, indicating the attenuation of the renal oxidative stress condition. The levels of malondialdehyde and angiotensin II (Ang II) in plasma and renal tissues, as well as the levels of aldosterone, 8-hydroxydeoxyguanosine, angiotensin II type 1 receptor and NADPH Oxidase-4 in the kidney tissue significantly decreased following XJEK treatment for 6 wk. In addition, the XJEK treatment groups revealed a significant upregulation in the activity of superoxide dismutase and in the total antioxidant capacity activity compared with those noted in the corresponding MI groups. CONCLUSION: These results demonstrated that progressive nephropathy in MI rats was associated with intrarenal activation of the renin-angiotensin-aldosterone system. Concomitantly, this process was associated with oxidative stress and impaired Nrf2 activation. The improvement in the severity of nephropathy by XJEK in this model may be associated with the reversal of these abnormalities.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/metabolismo , Rim/lesões , Rim/patologia , Infarto do Miocárdio/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Angiotensina II/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Cistatina C/metabolismo , Dano ao DNA , Regulação para Baixo/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , NADPH Oxidase 4/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Life Sci ; 231: 116563, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200003

RESUMO

AIMS: In the present study, we investigated the roles of renin-angiotensin system (RAS) activation and imbalance of matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in cold-induced stroke during chronic hypertension, as well as the protective effects of captopril and recombinant human TIMP-1 (rhTIMP-1). MAIN METHODS: Rats were randomly assigned to sham; 2-kidney, 2-clip (2K-2C); 2K-2C + captopril, and 2K-2C + rhTIMP-1 groups. After blood pressure values had stabilized, each group was randomly divided into an acute cold exposure (ACE) group (12-h light at 22 °C/12-h dark at 4 °C) and a non-acute cold exposure (NACE) group (12-h light/12-h dark at 22 °C), each of which underwent three cycles of exposure. Captopril treatment was administered via gavage (50 mg/kg/d), while rhTIMP-1 treatment was administered via the tail vein (60 µg/kg/36 h). KEY FINDINGS: In the 2K-2C group, angiotensin II (AngII) and MMP-9 levels increased in both the plasma and cortex, while no such changes in TIMP-1 expression were observed. Cold exposure further upregulated AngII and MMP-9 levels and increased stroke incidence. Captopril and rhTIMP-1 treatment inhibited MMP-9 expression and activation and decreased stroke incidence in response to cold exposure. SIGNIFICANCE: The present study is the first to demonstrate that cold exposure exacerbates imbalance between MMP-9 and TIMP-1 by activating the RAS, which may be critical in the initiation of stroke during chronic hypertension. In addition, our results suggest that captopril and rhTIMP-1 exert protective effects against cold-induced stroke by ameliorating MMP-9/TIMP-1 imbalance.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Sistema Renina-Angiotensina/fisiologia , Acidente Vascular Cerebral/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Captopril/metabolismo , Captopril/farmacologia , Proteínas de Ciclo Celular/metabolismo , Temperatura Baixa/efeitos adversos , Humanos , Rim/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Sistema Renina-Angiotensina/genética , Acidente Vascular Cerebral/fisiopatologia , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Inibidor Tecidual de Metaloproteinase-2
15.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100876

RESUMO

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1-PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. METHODS: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5-33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. RESULTS: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. CONCLUSION: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.


Assuntos
Restrição Calórica/métodos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Angiotensina II/metabolismo , Animais , Glicemia , Carbazóis/farmacologia , Cardiomegalia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Masculino , Malondialdeído/sangue , Mesoporfirinas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Protoporfirinas/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo
16.
Am J Physiol Regul Integr Comp Physiol ; 316(6): R776-R782, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042418

RESUMO

Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male Balb/c mice were divided into three groups, sedentary, swimming twice a day without overload (T2), and swimming three times a day with a 2% body weight overload (T3), totaling 6 wk of training. Both training groups developed similar cardiac hypertrophy, but only T3 mice improved their oxidative capacity. We observed that T2 had increased levels of MASR, which was followed by the activation of its main downstream protein AKT; meanwhile, AT1R and its main downstream protein ERK remained unchanged. Furthermore, no change was observed regarding the levels of angiotensin peptides, in either group. In addition, we observed no change in the ratio of expression of the myosin heavy chain ß-isoform to that of the α-isoform. Fibrosis was not observed in any of the groups. In conclusion, our results suggest that increasing exercise volume and intensity did not induce a pathological hypertrophy phenotype, but instead improved the oxidative capacity, and this process might have the participation of the RAS alternative axis.


Assuntos
Cardiomegalia/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Cardiomegalia/fisiopatologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Fragmentos de Peptídeos/metabolismo , Condicionamento Físico Animal , Receptor Tipo 1 de Angiotensina/metabolismo , Natação , Remodelação Ventricular/fisiologia
17.
Nat Commun ; 10(1): 2145, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086184

RESUMO

Although angiotensin II (AngII) is known to cause renal injury and fibrosis, the underlying mechanisms remain poorly characterized. Here we show that hypertensive nephropathy (HN) patients and AngII-infused mice exhibit elevated levels of circulating miR103a-3p. We observe a positive correlation between miR-103a-3p levels and AngII-induced renal dysfunction. miR-103a-3p suppresses expression of the sucrose non-fermentable-related serine/threonine-protein kinase SNRK in glomerular endothelial cells, and glomeruli of HN patients and AngII-infused mice show reduced endothelial expression of SNRK. We find that SNRK exerts anti-inflammatory effects by interacting with activated nuclear factor-κB (NF-κB)/p65. Overall, we demonstrate that AngII increases circulating miR-103a-3p levels, which reduces SNRK levels in glomerular endothelial cells, resulting in the over-activation of NF-κB/p65 and, consequently, renal inflammation and fibrosis. Together, our work identifies miR-103a-3p/SNRK/NF-κB/p65 as a regulatory axis of AngII-induced renal inflammation and fibrosis.


Assuntos
Angiotensina II/metabolismo , Glomerulonefrite/patologia , Hipertensão Renal/patologia , Glomérulos Renais/patologia , MicroRNAs/metabolismo , Nefrite/patologia , Proteínas Serina-Treonina Quinases/genética , Adulto , Angiotensina II/administração & dosagem , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibrose , Glomerulonefrite/sangue , Glomerulonefrite/genética , Glomerulonefrite/urina , Voluntários Saudáveis , Humanos , Hipertensão Renal/sangue , Hipertensão Renal/genética , Hipertensão Renal/urina , Glomérulos Renais/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , MicroRNAs/urina , Pessoa de Meia-Idade , Nefrite/sangue , Nefrite/genética , Nefrite/urina , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição RelA/metabolismo
18.
Mol Med Rep ; 19(6): 4553-4560, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059021

RESUMO

Cardiac fibrosis secondary to long­term hypertension is known to promote cardiac dysfunction; however, few therapeutic agents are available for the treatment of this condition in clinical practice. The heptapeptide alamandine (Ala) has recently been identified as a component of the renin­angiotensin system (RAS), which exerts a protective effect against cardiac hypertrophy; however, it is unknown whether Ala may also be useful for the treatment of cardiac fibrosis. In the present study, the potential therapeutic effects of Ala on long­term hypertension­induced cardiac fibrosis were investigated in an aged, spontaneous hypertensive rat model. Weekly blood pressure (BP) measurements revealed that daily Ala treatment significantly decreased the systolic, diastolic and mean arterial BP compared with the control. Of note, the observed reduction in BP in Ala­treated animals markedly differed to that observed in rats treated with hydralazine (Hyd). Echocardiography further demonstrated that Ala treatment decreased the ratio of left ventricle mass to body weight, and alleviated structural and functional parameters associated with cardiac fibrosis, including left ventricular volume, ejection fraction and fractional shortening compared with the control and Hyd­treated groups. Furthermore, Ala deceased the density of cardiac fibrosis, as assessed by Masson and Sirius red staining; reduced expression of fibrotic proteins, including connective tissue growth factor, collagen I (COL1A1) and matrix metalloproteinase 9, was also observed. In addition, Ala treatment further decreased the expression of angiotensin II­induced fibrotic markers at the mRNA and protein levels in cultured cardiac fibroblasts; Ala­mediated inhibition of COL1A1 expression and Akt phosphorylation was inhibited via the Mas­related G protein receptor antagonist, PD123319. Collectively, the findings of the present study suggest that Ala is an effective anti­hypertensive peptide that can attenuate cardiac dysfunction and fibrosis induced by chronic hypertension, independent of BP.


Assuntos
Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Cardiomegalia/etiologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrose/etiologia , Ventrículos do Coração/metabolismo , Hipertensão/complicações , Imidazóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina
19.
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
20.
Physiol Res ; 68(2): 329-334, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31037948

RESUMO

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Hipertensão/fisiopatologia , Renina/metabolismo , Sistema Nervoso Simpático/fisiologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/fisiologia , Citocromo P-450 CYP1A1/genética , Hipertensão/genética , Masculino , Ratos , Ratos Transgênicos , Renina/genética , Sistema Renina-Angiotensina/fisiologia , Vasoconstrição/fisiologia
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