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1.
Mutat Res ; 852: 503167, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32265040

RESUMO

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.


Assuntos
Angiotensinogênio/genética , Reparo do DNA , Instabilidade Genômica , Lactoilglutationa Liase/genética , Proteínas dos Microfilamentos/genética , Insuficiência Renal Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensinogênio/metabolismo , Estudos de Casos e Controles , Ensaio Cometa , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Lactoilglutationa Liase/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Testes para Micronúcleos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
2.
Am J Physiol Regul Integr Comp Physiol ; 318(5): R855-R869, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186897

RESUMO

Angiotensin II (ANG II) Agtr1a receptor (AT1A) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor (Lepr) and agouti-related peptide (Agrp). Agtr1a expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT1A signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (Agt, encoding AGT) with mice expressing Cre-recombinase via the Lepr or Agrp promoters to cause cell-specific deletions of Agt (AgtLepr-KO and AgtAgrp-KO mice, respectively). AgtLepr-KO mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, AgtAgrp-KO mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body Agt deficiency or Agt disruption in albumin (Alb)-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult AgtAgrp-KO mice exhibited normal circulating AGT protein and hepatic Agt mRNA expression but reduced Agt mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that Agrp and Alb are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both Agrp-Cre and Alb-Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of Agt is critically required for normal renal development and survival.


Assuntos
Glândulas Suprarrenais/metabolismo , Proteína Relacionada com Agouti/metabolismo , Angiotensinogênio/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Metabolismo Energético , Rim/metabolismo , Receptores para Leptina/metabolismo , Glândulas Suprarrenais/crescimento & desenvolvimento , Proteína Relacionada com Agouti/deficiência , Proteína Relacionada com Agouti/genética , Angiotensinogênio/deficiência , Angiotensinogênio/genética , Animais , Núcleo Arqueado do Hipotálamo/crescimento & desenvolvimento , Comunicação Autócrina , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Rim/crescimento & desenvolvimento , Masculino , Camundongos Knockout , Miocárdio/metabolismo , Comunicação Parácrina , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Albumina Sérica/genética , Albumina Sérica/metabolismo , Transdução de Sinais
3.
Curr Opin Nephrol Hypertens ; 29(2): 180-189, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31895165

RESUMO

PURPOSE OF REVIEW: To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. RECENT FINDINGS: Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease. SUMMARY: Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence.


Assuntos
Angiotensinogênio/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Angiotensinogênio/genética , Animais , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos
4.
PLoS One ; 15(1): e0227507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929561

RESUMO

Bovine respiratory disease (BRD) is a multifactorial disease complex and the leading infectious disease in post-weaned beef cattle. Clinical manifestations of BRD are recognized in beef calves within a high-risk setting, commonly associated with weaning, shipping, and novel feeding and housing environments. However, the understanding of complex host immune interactions and genomic mechanisms involved in BRD susceptibility remain elusive. Utilizing high-throughput RNA-sequencing, we contrasted the at-arrival blood transcriptomes of 6 beef cattle that ultimately developed BRD against 5 beef cattle that remained healthy within the same herd, differentiating BRD diagnosis from production metadata and treatment records. We identified 135 differentially expressed genes (DEGs) using the differential gene expression tools edgeR and DESeq2. Thirty-six of the DEGs shared between these two analysis platforms were prioritized for investigation of their relevance to infectious disease resistance using WebGestalt, STRING, and Reactome. Biological processes related to inflammatory response, immunological defense, lipoxin metabolism, and macrophage function were identified. Production of specialized pro-resolvin mediators (SPMs) and endogenous metabolism of angiotensinogen were increased in animals that resisted BRD. Protein-protein interaction modeling of gene products with significantly higher expression in cattle that naturally acquire BRD identified molecular processes involving microbial killing. Accordingly, identification of DEGs in whole blood at arrival revealed a clear distinction between calves that went on to develop BRD and those that resisted BRD. These results provide novel insight into host immune factors that are present at the time of arrival that confer protection from BRD.


Assuntos
Doenças dos Bovinos/diagnóstico , Resistência à Doença/genética , Perfilação da Expressão Gênica/métodos , Doenças Respiratórias/diagnóstico , Angiotensinogênio/metabolismo , Animais , Estudos de Casos e Controles , Bovinos , Doenças dos Bovinos/sangue , Doenças dos Bovinos/genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Mapas de Interação de Proteínas/genética , RNA/química , RNA/genética , RNA/metabolismo , Doenças Respiratórias/sangue , Doenças Respiratórias/genética , Análise de Sequência de RNA , Transdução de Sinais/genética
5.
Comput Biol Chem ; 84: 107199, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31931433

RESUMO

Angiotensinogen (AGT) is a key component of renin-angiotensin-aldosterone system (RAAS), which plays central role in blood pressure homeostasis. Association of AGT polymorphisms have been investigated in different ethnic populations in variety of cardiovascular and non-cardiovascular conditions. In this study, 354 non-synonymous SNPs (nsSNPs) of AGT were evaluated to predict damaging and structurally important variants. Majority of the deleterious nsSNPs occurred in the evolutionary conserved regions. Several of these nsSNPs were found to affect post-translational modifications like methylation, glycosylation, phosphorylation, ubiquitination etc. Structural evaluations predicted 19 variants as destabilizing and some of them were also predicted to destabilize the renin-AGT interaction. Therefore, the present computational investigation predicted pathogenic and functionally important variants of human AGT gene. The study has also shown that AGT deregulation is associated with survival outcome in patients with gastric and breast cancer, using microarray gene expression profile. Furthermore, the computationally screened nsSNPs can be analyzed in population based genotyping studies and may help futuristic drug development in the area of AGT pharmacogenomics.


Assuntos
Angiotensinogênio/genética , Polimorfismo de Nucleotídeo Único , Sequência de Aminoácidos , Angiotensinogênio/química , Humanos , Neoplasias/enzimologia , Neoplasias/fisiopatologia , Processamento de Proteína Pós-Traducional , Relação Estrutura-Atividade , Taxa de Sobrevida , Termodinâmica
6.
Am J Physiol Renal Physiol ; 318(1): F67-F75, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682172

RESUMO

Renal proximal tubular angiotensinogen (AGT) is increased by hyperglycemia (HG) in diabetes mellitus, which augments intrarenal angiotensin II formation, contributing to the development of hypertension and kidney injury. Sodium-glucose cotransporter 2 (SGLT2) is abundantly expressed in proximal tubular cells (PTCs). The present study investigated the effects of canagliflozin (CANA), a SGLT2 inhibitor, on HG-induced AGT elevation in cultured PTCs. Mouse PTCs were treated with 5-25 mM glucose. CANA (0-10 µM) was applied 1 h before glucose treatment. Glucose (10 mM) increased AGT mRNA and protein levels at 12 h (3.06 ± 0.48-fold in protein), and 1 and 10 µM CANA as well as SGLT2 shRNA attenuated the AGT augmentation. CANA did not suppress the elevated AGT levels induced by 25 mM glucose. Increased AGT expression induced by treatment with pyruvate, a glucose metabolite that does not require SGLT2 for uptake, was not attenuated by CANA. In HG-treated PTCs, intracellular reactive oxygen species levels were elevated compared with baseline (4.24 ± 0.23-fold), and these were also inhibited by CANA. Furthermore, tempol, an antioxidant, attenuated AGT upregulation in HG-treated PTCs. HG-induced AGT upregulation was not inhibited by an angiotensin II receptor antagonist, indicating that HG stimulates AGT expression in an angiotensin II-independent manner. These results indicate that enhanced glucose entry via SGLT2 into PTCs elevates intracellular reactive oxygen species generation by stimulation of glycolysis and consequent AGT augmentation. SGLT2 blockade limits HG-induced AGT stimulation, thus reducing the development of kidney injury in diabetes mellitus.


Assuntos
Angiotensinogênio/metabolismo , Canagliflozina/farmacologia , Glucose/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
7.
Iran J Kidney Dis ; 13(6): 372-379, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31880583

RESUMO

INTRODUCTION: Urinary angiotensinogen (uAGT) has been described as a novel biomarker of acute kidney injury (AKI) and chronic kidney disease (CKD). Renal interstitial inflammatory cell infiltration is a common renal pathological feature of AKI and CKD. However, the correlation between uAGT and renal interstitial inflammatory cell infiltration is unknown. The aim of this study was to analyze the expression of uAGT, its relationship with interstitial inflammatory cell infiltration, and prognosis in patients with renal insufficiency. METHODS: The expression of uAGT, urinary kidney injury molecule 1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were examined by enzyme-linked immunosorbent assay (ELISA) at baseline and kidney pathology was evaluated at the same time. RESULTS: Sixty-five patients with renal insufficiency and 12 healthy controls were enrolled. uAGT, uKIM-1, and uNGAL levels were significantly higher compared with healthy participants. uAGT showed the strongest correlation with interstitial inflammatory cell infiltration (r = 0.366, P < .05). uAGT level was able to identify interstitial inflammatory cell infiltration with greater accuracy (AUC = 0.664, P < .05) than other urinary biomarkers. After a median follow-up of 22 months, 15 patients reached the composite renal endpoint. Kaplan meier survival curves followed by multivariate cox proportional hazards regression analysis showed that uAGT (> 166.8 ng/mg creatinine) independently predicted higher risk of the endpoint. CONCLUSION: uAGT may be used as a non-invasive biomarker of interstitial inflammatory cell infiltration and a strong predictor of renal prognosis in patients with renal insufficiency.


Assuntos
Lesão Renal Aguda/urina , Angiotensinogênio/urina , Biomarcadores/urina , Insuficiência Renal Crônica/urina , Lesão Renal Aguda/complicações , Adulto , Estudos de Casos e Controles , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia
8.
Andrologia ; 51(11): e13421, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31637747

RESUMO

Many researchers have shown that renin-angiotensin system (RAS) is involved in various important aspects of male reproduction. In this study, we assessed whether abnormal levels of seminal angiotensinogen (AGT) may be associated with semen parameters in infertile males. A total of 115 male patients were recruited, and semen parameters, seminal AGT and the electrolytes including K+ , Na+ , Cl- , P and Ca were evaluated. According to the World Health Organization (WHO) 2010 criteria, the patients were divided into two groups: G1 group with normal semen parameters (n = 42) and G2 group with subnormal semen parameters (n = 73). The level of seminal AGT was significantly higher in G2 group compared with G1 group. Moreover, the level of AGT was negatively correlated with the percentage of total motility (r = -.322, p = .000), progressive motility (PR) (r = -.339, p = .000) and morphologically normal forms (r = -.263, p = .004). This study suggests that elevated seminal AGT level is associated with increased risk of asthenospermia and teratozoospermia.


Assuntos
Angiotensinogênio/metabolismo , Infertilidade Masculina/metabolismo , Sêmen/metabolismo , Motilidade Espermática , Adulto , Humanos , Infertilidade Masculina/patologia , Masculino , Pessoa de Meia-Idade , Espermatozoides/patologia
9.
J Renin Angiotensin Aldosterone Syst ; 20(4): 1470320319881932, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31642377

RESUMO

OBJECTIVE: The renin-angiotensin system gene has been implicated in the progression of colorectal cancer. Nevertheless, the details of that role remain controversial. We performed a meta-analysis to investigate the correlation between renin-angiotensin system gene polymorphisms and colorectal cancer. METHODS: We retrieved relevant studies from PubMed and Embase. Subsequently, fixed or random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We identified six studies of the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism, and two studies of the angiotensinogen M235T polymorphism. The angiotensin-converting enzyme I/D polymorphism did not significantly correlate with colorectal cancer risk in the total population (DD vs. II: OR 0.77, 95% CI 0.39-1.50; DI vs. II: OR 1.05, 95% CI 0.85-1.30; dominant model: OR 0.94, 95% CI 0.68-1.31; recessive model: OR 1.01, 95% CI 0.80-1.27). Similarly, the angiotensinogen M235T polymorphism was not associated with colorectal cancer risk (TT vs. MM: OR 1.38, 95% CI 0.52-3.67; TM vs. MM: OR 1.19, 95% CI 0.96-1.47; dominant model: OR 1.28, 95% CI 0.77-2.14; recessive model: OR 1.17, 95% CI 0.53-2.59). CONCLUSION: Our findings suggest that the angiotensin-converting enzyme I/D and angiotensinogen M235T polymorphisms are unlikely to correlate with colorectal cancer.


Assuntos
Angiotensinogênio/genética , Neoplasias Colorretais/genética , Peptidil Dipeptidase A/genética , Sistema Renina-Angiotensina/genética , Humanos , Mutação INDEL , Polimorfismo Genético
10.
J Physiol Pharmacol ; 70(4)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31642813

RESUMO

The tissue renin-angiotensin system (RAS) plays an important role in the development and progression of many diseases. It has been confirmed that angiotensin II (ANG II) participates in the proliferation and angiogenesis of breast cancer. Moreover, some RAS dysregulations in cancer have been observed. Recent studies on the role of two opposite axes of angiotensinogen metabolism - ACE (angiotensin-converting enzyme)/ANGII/AT1R (angiotensin receptor type 1) and ACE-2/ANG 1-7/MAS (mitochondrial assembly) - indicate their importance in tumor growth and invasion, but studies describing the metabolic pathways in breast cancer and the role of newer angiotensins, such as ANG 1-12, remain lacking. In this study, the metabolism of angiotensinogen fragments in three breast cancer lines, namely, MDA-MB-231, MCF-7, and T-47D, compared with normal breast tissue cells (PCS-600) was estimated. Incubation of the cancer cells with angiotensinogen resulted in the prevalent formation of ANG 1-7. A difference in the ability to form ANG II was observed between cell lines. In normal breast cells, the strong predominance of the ACE-2/ANG 1-7/MAS pathway was detected. In cancer cells, differences in angiotensinogen metabolism depending on cancer line were observed; the prevalence of the ACE/ANG II/AT1R pathway was shown. Expressions of the RAS component were dysregulated in cancer cells and differed between cell lines. In conclusion, the ability of breast cancer cells to produce numerous angiotensin peptide metabolites was demonstrated. The metabolism of angiotensinogen differed between various types of breast cancer cells. The obtained results indicate the greater importance of the classical pathway - ACE/ANG II/AT1R - in breast cancer cells. The production of ANG 1-12 seems to be marginal in breast tissue, but a tendency for the higher formation of this peptide in cancer cells was observed. The production of ANG 1-7 was significantly lower in cancer cells, whereas the expression of MAS receptor was higher than that in the control. This finding suggests that substances with MAS receptor agonist activity could be useful in the treatment of breast cancer, but this requires further investigations.


Assuntos
Angiotensina I/metabolismo , Angiotensinogênio/metabolismo , Neoplasias da Mama/metabolismo , Fragmentos de Peptídeos/metabolismo , Mama/citologia , Mama/metabolismo , Linhagem Celular , Feminino , Humanos , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
11.
Anticancer Res ; 39(10): 5525-5530, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570446

RESUMO

BACKGROUND/AIM: Basal cell carcinoma (BCC) has been genetically associated with an increased expression of angiotensin-converting enzyme (ACE), an important factor of the renin-angiotensin system which produces vasoconstrictor angiotensin II. Other factors of this system include angiotensinogen (AGT) and angiotensin receptors AGTR1, AGTR2. We investigated the possible association of BCC with genetic variability in the AGT, AGTR1 and AGTR2 genes. MATERIALS AND METHODS: DNA samples of 190 Greeks were studied, including 91 patients with BCC and 99 matched healthy controls. Molecular genotyping of patients and controls was performed for the polymorphisms AGT M235T, AGTR1 A1166C and AGTR2 G1675A. RESULTS: The mutant T allele that increases AGT gene expression was detected in two-fold increased frequency in BCC patients in comparison to healthy controls (p <0.001). On the contrary, no significant difference was observed in AGTR1 and AGTR2 variants between patients and controls. CONCLUSION: Increased expression of AGT may be associated with BCC.


Assuntos
Carcinoma Basocelular/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Angiotensinogênio/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética
12.
Nutrients ; 11(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546789

RESUMO

The systemic renin-angiotensin system (RAS) is an important regulator of body fluid and sodium homeostasis. Angiotensin II (AngII) is a key active product of the RAS. We previously revealed that circulating AngII suppresses amiloride-sensitive salt taste responses and enhances the responses to sweet compounds via the AngII type 1 receptor (AT1) expressed in taste cells. However, the molecular mechanisms underlying the modulation of taste function by AngII remain uncharacterized. Here we examined the expression of three RAS components, namely renin, angiotensinogen, and angiotensin-converting enzyme-1 (ACE1), in mouse taste tissues. We found that all three RAS components were present in the taste buds of fungiform and circumvallate papillae and co-expressed with αENaC (epithelial sodium channel α-subunit, a salt taste receptor) or T1R3 (taste receptor type 1 member 3, a sweet taste receptor component). Water-deprived mice exhibited significantly increased levels of renin expression in taste cells (p < 0.05). These results indicate the existence of a local RAS in the taste organ and suggest that taste function may be regulated by both locally-produced and circulating AngII. Such integrated modulation of peripheral taste sensitivity by AngII may play an important role in sodium/calorie homeostasis.


Assuntos
Regulação da Expressão Gênica/fisiologia , Glutamato Descarboxilase/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/fisiologia , Paladar/fisiologia , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Feminino , Glutamato Descarboxilase/genética , Proteínas de Fluorescência Verde , Masculino , Camundongos , Receptores Acoplados a Proteínas-G/genética , Renina/genética , Renina/metabolismo , Papilas Gustativas/química
13.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(8): 997-1002, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31484268

RESUMO

Objective: To explore the association between preeclampsia/eclampsia and maternal and fetal angiotensinogen SNPs. Methods: From January 2008 to October 2015, a case-parents/mother-control designed study was conducted among 347 preeclampsia/eclampsia cases and 700 controls to collect related information on their demographic characteristics and to detect the related angiotensinogen SNPs' genotypes. Both log-linear and unconditional logistic regression methods were employed to investigate the genetic effects of maternal/fetal angiotensinogen SNPs on preeclampsia/eclampsia. Multivariate binary unconditional logistic regression model and covariance were used to analyze the relationship between BMI before pregnancy, weight gain during pregnancy and overweight and obesity in preschool children. Results: Both fetal angiotensinogen rs3789679 GA and AA genotype were associated with the reduced risks of preeclampsia/eclampsia, with ORs as 0.73 (95%CI: 0.55-0.96) and 0.62 (95%CI: 0.39-0.98), respectively. For fetal angiotensinogen rs2493132, individuals that carrying the TT genotype, presented a positive association with the risk of preeclampsia/eclampsia, with OR as 1.60 (95%CI: 1.08-2.37). However, these associations were not statistically significant after the correction of the false discovery rate. It was observed that fetal rs3789679 could reduce the risk of preeclampsia/eclampsia (OR=0.73, 95%CI: 0.55-0.96) under the dominant model (GA+AA/GG) while fetal rs2493132 increased the risk of preeclampsia/eclampsia (OR=1.66, 95%CI: 1.13-2.44) under the recessive model (TT/CC+CT). Maternal rs5051 presented an association with preeclampsia/eclampsia (OR=1.33, 95%CI: 1.01-1.76) under the dominant model (TC+CC/TT). Conclusions: Results from the dominant model showed that both fetal rs3789679 GA and AA genotype reduced the risk of preeclampsia/eclampsia and maternal rs5051 TC while CC genotype increased the risk of preeclampsia/eclampsia. Fetal rs2493132 TT genotype seemed to be associated with the risk of preeclampsia/eclampsia under the recessive model.


Assuntos
Angiotensinogênio/genética , Eclampsia/genética , Polimorfismo de Nucleotídeo Único/genética , Pré-Eclâmpsia/genética , Angiotensinogênio/sangue , Estudos de Casos e Controles , Eclampsia/sangue , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pré-Eclâmpsia/sangue , Gravidez , Cuidado Pré-Natal
14.
Hypertension ; 74(4): 817-825, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422694

RESUMO

The BBSome-a complex consisting of 8 Bardet-Biedl syndrome proteins-is involved in the regulation of various cellular processes. Recently, the BBSome complex has emerged as an important regulator of cardiovascular function with implications for disease. In this study, we examined the role of the BBSome in vascular smooth muscle and its effects on the regulation of cardiovascular function. Smooth muscle-specific disruption of the BBSome through tamoxifen-inducible deletion of Bbs1 gene-a critical component of the BBSome complex-reduces relaxation and enhances contractility of vascular rings and increases aortic stiffness independent of changes in arterial blood pressure. Mechanistically, we demonstrate that smooth muscle Bbs1 gene deletion increases vascular angiotensinogen gene expression implicating the renin-angiotensin system in these altered cardiovascular responses. Additionally, we report that smooth muscle-specific Bbs1 knockout mice demonstrate enhanced ET-1 (endothelin-1)-induced contractility of mesenteric arteries-an effect reversed by blockade of the AT1 (angiotensin type 1 receptor) with losartan. These findings highlight the importance of the smooth muscle BBSome in the control of vascular function and arterial stiffness through modulation of renin-angiotensin system signaling.


Assuntos
Pressão Sanguínea/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Rigidez Vascular/fisiologia , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Aorta/fisiologia , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Vasodilatação/fisiologia
15.
Arch Endocrinol Metab ; 63(4): 402-410, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365628

RESUMO

OBJECTIVE: The increased prevalence of obesity and associated comorbidities, such as cardiovascular and metabolic diseases, has gained attention worldwide, and the renin-angiotensin system (RAS) has been pointed out as a possible link. Thus, the present study aimed to verify the possible association between angiotensinogen (AGT) or angiotensin-converting enzyme (ACE) polymorphisms with overweight and obesity in adults. SUBJECTS AND METHODS: The present investigation was a population-based cross-sectional study including 1,567 individuals from an urban area in Brazil. Anthropometric, clinical and biochemical parameters were evaluated, and all individuals were genotyped for the ACE I/D and AGT M/T polymorphisms. RESULTS: The prevalence of overweight was higher among men, whereas obesity was more prevalent among women. However, the frequency of ACE or AGT polymorphisms was similar among body mass index (BMI) categories. In addition, the mean age-adjusted BMI averages did not change significantly for ACE or AGT polymorphisms, regardless of sex or BMI category. The age-adjusted BMI average for the combination of ACE and AGT genotypes evidenced no significant differences regardless of sex or BMI categories. Results were similar when BMI was replaced by waist circumference (WC). CONCLUSIONS: We were not able to find any associations between BMI and WC (overweight/obesity) and ACE and AGT polymorphisms, indicating that the RAS system might not be involved in overweight and obesity, at least based on genetic backgrounds. However, further studies must measure RAS components to elucidate this question.


Assuntos
Obesidade/genética , Sobrepeso/genética , Polimorfismo Genético/genética , Sistema Renina-Angiotensina/genética , Adulto , Distribuição por Idade , Angiotensinogênio/genética , Pressão Sanguínea , Índice de Massa Corporal , Brasil , Estudos Transversais , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genética , Distribuição por Sexo , Circunferência da Cintura
16.
Eur J Pharmacol ; 862: 172629, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31449808

RESUMO

Congestive cardiac failure has become one of the major health challenges of the 21st century and new therapies are needed to address this problem. The concentration of vasoactive intestinal peptide (VIP) in the heart has been shown to decrease as fibrosis (the pathology leading to heart failure) increases and to become undetectable in end stage cardiomyopathy. We sought to determine whether replenishment of myocardial VIP might treat myocardial fibrosis and therefore represent a new therapeutic target. Wistar Kyoto rats on a high (4.4%) salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. Myocardial VIP concentration was measured by radioimmunoassay, fibrosis was quantitated by computerised histomorphometry and changes in pro-fibrotic mediators were measured by quantitative rt-PCR. Myocardial VIP increased significantly in VIP treated rats compared with vehicle treated controls (P < 0.01) while fibrosis in the VIP treated rats was significantly lower than in both the zero time control (P < 0.05) and the vehicle infused control (P < 0.0005). Although all six profibrotic mediators which were measured increased over the 4 week experimental period VIP infusion only affected angiotensinogen (Agt) and angiotensin receptor type 1a (AT1a) expression. In both instances VIP caused a significant decrease in messenger rna expression (Agt P < 0.01 and At1a P < 0.01) compared with vehicle infused controls. We conclude that VIP infusion increased myocardial VIP concentration and was able to reverse existing myocardial fibrosis suggesting a possible therapeutic role for a VIP based therapy in cardiac failure.


Assuntos
Cardiomiopatias/tratamento farmacológico , Miocárdio/patologia , Peptídeo Intestinal Vasoativo/administração & dosagem , Angiotensinogênio/análise , Angiotensinogênio/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Modelos Animais de Doenças , Fibrose , Humanos , Infusões Intravenosas , Masculino , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/análise , Receptor Tipo 1 de Angiotensina/metabolismo , Sódio na Dieta/efeitos adversos , Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/metabolismo
17.
Pregnancy Hypertens ; 18: 1-8, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442828

RESUMO

BACKGROUND: Changes in the renin-angiotensin-aldosterone system's (RAAS) activity due to different genetic variations could represent risk factors for the onset of preeclampsia. OBJECTIVE: To test and quantify the relationships of 8 RAAS gene polymorphisms (angiotensinogen (AGT)-M235T, AGT-T174M, angiotensin converting enzyme (ACE)-I/D, ACE8-A2350G, angiotensin II type 1 receptor (AGTR1)-A1166C, angiotensin II type 2 receptor (AGTR2)-C3123A, renin (REN)-G83A, aldosterone synthase (CYP11B2)-T344C) with susceptibility to early- (EOPE) and late-onset preeclampsia (LOPE). STUDY DESIGN: We performed polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) analysis in 217 pregnant women, of whom 87 pregnant women with EOPE/LOPE and 130 normal pregnant women. The relationship between the studied RASS gene polymorphisms and EOPE/LOPE was tested by multiple logistic regressions. RESULTS: The multivariate logistic regression analysis showed that AGT-M235T (adjusted OR = 4.63), AGT-T174M (adjusted OR = 4.13), REN-G83A (adjusted OR = 3) and CYP11B2-C344T (adjusted OR = 3.13) gene polymorphisms remained independent risk factors for EOPE. Moreover, ACE-I/D (adjusted OR = 4.04), ACE-A2350G (adjusted OR = 3.5), AGTR1-A1166C (adjusted OR = 2.73), and REN-G83A (adjusted OR = 2.67) polymorphisms remained independent risk factors for LOPE. The frequency of overweight was significantly different (p = 0.001) in pregnant women with EOPE, LOPE and the control group (LOPE:16, 29.6% vs. EOPE:12, 36.4% vs. control group:16, 12.3%). Pregnant women with EOPE had babies with a significantly lower mean birth weight (2067.9 ±â€¯887.9) in comparison to women with LOPE (mean ±â€¯SD: 2860.1 ±â€¯771.1, p < 0.001) and women with normal pregnancies, respectively (mean ±â€¯SD: 3324.9 ±â€¯484.9, p < 0.001). CONCLUSION: We confirmed the influence of the renin-angiotensin-aldosterone system through these 8 genetic variations on the onset of preeclampsia.


Assuntos
Angiotensinogênio/genética , Predisposição Genética para Doença , Placenta/metabolismo , Pré-Eclâmpsia/genética , Cuidado Pré-Natal , Sistema Renina-Angiotensina/genética , Adulto , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Gravidez , Fatores de Risco , Romênia
18.
J Renin Angiotensin Aldosterone Syst ; 20(3): 1470320319862662, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379247

RESUMO

BACKGROUND: The most common disease associated with the presence of kidney cysts in the population is autosomal dominant polycystic kidney disease (ADPKD), which finally leads to end-stage renal disease. METHOD: The study evaluated serum and urinary concentration of angiotensinogen (AGT) and interleukin 18 (IL-18) in a group of 39 children with renal cysts of different aetiology. RESULTS: Serum and urinary AGT concentration in children with renal cysts was higher compared to controls, regardless of the underlying background and gender. Serum IL-18 concentration was lower, in contrast, and the concentration of IL-18 in the urine did not differ between affected and healthy children. Negative correlation between urinary IL-18 concentration and systolic and mean arterial blood pressure was noted. CONCLUSIONS: Higher AGT levels in serum and urine in children with renal cysts may indicate the activation of the renin-angiotensin-aldosterone system, including its intrarenal part, even before the onset of hypertension. Lower serum concentration of IL-18 in children with kidney cysts may indicate the loss of the protective role of this cytokine with the occurrence of hypertension.


Assuntos
Angiotensinogênio/sangue , Angiotensinogênio/urina , Interleucina-18/sangue , Interleucina-18/urina , Doenças Renais Císticas/sangue , Doenças Renais Císticas/urina , Adolescente , Biomarcadores/sangue , Biomarcadores/urina , Pressão Sanguínea , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Taxa de Filtração Glomerular , Humanos , Lactente , Doenças Renais Císticas/fisiopatologia , Masculino , Adulto Jovem
19.
Med Sci Monit ; 25: 5986-5991, 2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401645

RESUMO

BACKGROUND Sepsis is a devastating medical condition. In the USA, about 745 000 people are diagnosed with sepsis annually. Although many anti-inflammatory drugs have been used to manage sepsis, the treatment success rate is very low. This study was undertaken to examine the protective effects of naringenin on sepsis-induced kidney injury in rats. MATERIAL AND METHODS Sepsis was induced in Wistar albino rats by cecal ligation and puncture methods. Histological analysis was performed with hematoxylin and eosin (HE) staining. Reactive oxygen species (ROS) levels were determined by flow cytometery. TUNEL assay was used to demonstrate apoptosis. Sandwich ELISA method was used for the determination of urinary angiotensinogen, and protein expression was determined by Western blot analysis. RESULTS We found that naringenin decreased atrophy in the glomerulus and enabled maintenance of the capsule area and normal tubular cavity of the septic rats. Admistration of naringenin at the dosage of 10 and 20 mg/kg to sepsis rats caused significant reduction in the sepsis-induced apoptosis of kidney cells, accompanied by decrease in Bax and increase in Bcl-2 expression. Moreover, naringenin also decreased the ROS levels in septic rats and downregulated the expression of SOD, CAT, and APX. The effects of naringenin were also examined on the levels of urinary angiotensinogen in sepsis rats. We found that naringenin caused a significant decrease in urinary angiotensinogen levels of septic rats. CONCLUSIONS Naringenin appears to have potential in the treatment of sepsis.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Flavanonas/farmacologia , Sepse/tratamento farmacológico , Angiotensinogênio/urina , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Ceco/patologia , Modelos Animais de Doenças , Rim/patologia , Glomérulos Renais/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Sistema Urinário/patologia
20.
J Strength Cond Res ; 33(9): 2344-2351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343553

RESUMO

Pickering, C, Suraci, B, Semenova, EA, Boulygina, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Leonska-Duniec, A, Pajak, B, Chycki, J, Moska, W, Lulinska-Kuklik, E, Dornowski, M, Maszczyk, A, Bradley, B, Kana-ah, A, Cieszczyk, P, Generozov, EV, and Ahmetov, II. A genome-wide association study of sprint performance in elite youth football players. J Strength Cond Res 33(9): 2344-2351, 2019-Sprint speed is an important component of football performance, with teams often placing a high value on sprint and acceleration ability. The aim of this study was to undertake the first genome-wide association study to identify genetic variants associated with sprint test performance in elite youth football players and to further validate the obtained results in additional studies. Using micro-array data (600 K-1.14 M single nucleotide polymorphisms [SNPs]) of 1,206 subjects, we identified 12 SNPs with suggestive significance after passing replication criteria. The polymorphism rs55743914 located in the PTPRK gene was found as the most significant for 5-m sprint test (p = 7.7 × 10). Seven of the discovered SNPs were also associated with sprint test performance in a cohort of 126 Polish women, and 4 were associated with power athlete status in a cohort of 399 elite Russian athletes. Six SNPs were associated with muscle fiber type in a cohort of 96 Russian subjects. We also examined genotype distributions and possible associations for 16 SNPs previously linked with sprint performance. Four SNPs (AGT rs699, HSD17B14 rs7247312, IGF2 rs680, and IL6 rs1800795) were associated with sprint test performance in this cohort. In addition, the G alleles of 2 SNPs in ADRB2 (rs1042713 & rs1042714) were significantly over-represented in these players compared with British and European controls. These results suggest that there is a genetic influence on sprint test performance in footballers, and identifies some of the genetic variants that help explain this influence.


Assuntos
Desempenho Atlético/fisiologia , Grupo com Ancestrais do Continente Europeu/genética , Corrida/fisiologia , Futebol/fisiologia , 17-Hidroxiesteroide Desidrogenases/genética , Aceleração , Adolescente , Alelos , Angiotensinogênio/genética , Criança , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator de Crescimento Insulin-Like II/genética , Interleucina-6/genética , Masculino , Polônia , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores Adrenérgicos beta 2/genética , Federação Russa , Reino Unido , Adulto Jovem
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