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1.
Int J Mol Sci ; 24(22)2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-38003316

RESUMO

ANRIL (Antisense Noncoding RNA in the INK4 Locus), also named CDKN2B-AS1, is a long non-coding RNA with outstanding functions that regulates genes involved in atherosclerosis development. ANRIL genotypes and the expression of linear and circular isoforms have been associated with coronary artery disease (CAD). The CDKN2A and the CDKN2B genes at the CDKN2A/B locus encode the Cyclin-Dependent Kinase inhibitor protein (CDKI) p16INK4a and the p53 regulatory protein p14ARF, which are involved in cell cycle regulation, aging, senescence, and apoptosis. Abnormal ANRIL expression regulates vascular endothelial growth factor (VEGF) gene expression, and upregulated Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis by activating the NF-κB signaling pathway. Here, we explored associations between determinations of the linear, circular, and linear-to-circular ANRIL gene expression ratio, CDKN2A, VEGF and its receptor kinase insert domain-containing receptor (KDR) and cardiovascular risk factors and all-cause mortality in high-risk coronary patients before they undergo coronary artery bypass grafting surgery (CABG). We found that the expression of ANRIL isoforms may help in the prediction of CAD outcomes. Linear isoforms were correlated with a worse cardiovascular risk profile while the expression of circular isoforms of ANRIL correlated with a decrease in oxidative stress. However, the determination of the linear versus circular ratio of ANRIL did not report additional information to that determined by the evaluation of individual isoforms. Although the expressions of the VEFG and KDR genes correlated with a decrease in oxidative stress, in binary logistic regression analysis it was observed that only the expression of linear isoforms of ANRIL and VEGF significantly contributed to the prediction of the number of surgical revascularizations.


Assuntos
Doença da Artéria Coronariana , RNA Longo não Codificante , Humanos , Doença da Artéria Coronariana/genética , Fator A de Crescimento do Endotélio Vascular , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , NF-kappa B/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Isoformas de Proteínas/genética
3.
Clin Kidney J ; 12(6): 767-770, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31807289

RESUMO

In chronic kidney disease (CKD), referral to nephrology is based on Kidney Disease: Improving Global Outcomes 2012 guidelines and is generally indicated when the estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m2 or when there is a rapid decline of eGFR, elevated urinary albumin:creatinine ratio (>300 mg/g) or other 'alert' signs such as the presence of urinary red blood cell casts. Since eGFR declines with ageing in otherwise healthy individuals, we propose that the eGFR threshold for nephrology referral should be adjusted according to age. According to current recommendations, young patients without rapidly progressing CKD are referred more often to nephrology when CKD is more severe, compared with age-matched controls with normal eGFRs, than elderly CKD patients. In this commentary, we discuss the age factor and other specific situations not considered in current guidelines for nephrology referral of CKD patients.

4.
J Ren Nutr ; 28(6): 428-434, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29983232

RESUMO

OBJECTIVE: To study whether the score proposed by the International Society of Renal Nutrition and Metabolism to define the protein energy wasting (PEW) syndrome has diagnostic validity in patients undergoing dialysis. DESIGN AND METHODS: Cross-sectional study including 468 prevalent hemodialysis patients from Canary Islands, Spain. Individual PEW syndrome criteria and the number of PEW syndrome categories were related to other objective markers of PEW using linear and logistic regression analyses: subjective global assessment, handgrip strength, bioimpedance-assessed body composition, and levels of high-sensitivity C-reactive protein. RESULTS: Study participants (34% women) had a median age of 66 years, 37 months of maintenance dialysis, and 50% were diabetics. About 23% of patients had PEW (≥3 PEW categories), and 68% were at risk of PEW (1-2 PEW categories). Low prealbumin was the most frequently found derangement (52% of cases), followed by low albumin (46%), and low protein intake (35%). Across higher number of PEW syndrome categories, patients showed a longer dialysis vintage and had lower creatinine, triglycerides, and transferrin (P for trend <.001 for all). All nutritional assessments not included in the PEW definition worsened across higher number of PEW categories. In multivariable regression analyses, there was a linear inverse relationship between muscle and fat mass as well as handgrip strength with the number of PEW syndrome categories. Likewise, the proportion of subjective global assessment-defined malnutrition and serum concentration of C-reactive protein gradually increased despite adjustment for confounders (P for trend <.05 for all). CONCLUSION: The PEW score reflects systemic inflammation, malnutrition and wasting among dialysis patients and may thus be used for diagnostic purposes.


Assuntos
Desnutrição Proteico-Calórica/complicações , Desnutrição Proteico-Calórica/diagnóstico , Desnutrição Proteico-Calórica/fisiopatologia , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Idoso , Proteína C-Reativa , Estudos Transversais , Impedância Elétrica , Feminino , Força da Mão/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Espanha
5.
Nefrologia ; 34(3): 302-16, 2014 May 21.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-24798565

RESUMO

The new Kidney Disease: Improving Global Outcomes (KDIGO) international guidelines on chronic kidney disease (CKD) and the management of blood pressure (BP) in CKD patients are an update of the corresponding 2002 and 2004 KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines. The documents aim to provide updated guidelines on the assessment, management and treatment of patients with CKD. The first guidelines retain the 2002 definition of CKD but present an improved prognosis classification. Furthermore, concepts about prognosis of CKD, recommendations for management of patients, and criteria for referral to the nephrologist have been updated. The second guideline retains the <130/80 mm Hg-goal for management of BP in patients with CKD presenting increased albuminuria or proteinuria (albumin-to-creatinine ratio 30-300 mg/g, and >300 mg/g, respectively) but recommends a less-strict goal of <140/90 mm Hg in patients with normoalbuminuria. The development of the guidelines followed a predetermined process in which the evidence available was reviewed and assessed. Recommendations on management and treatment are based on the systematic review of relevant studies. The GRADE system (Grading of Recommendations Assessment, Development and Evaluation) was used to assess the quality of evidence and issue the grade of recommendation. Areas of uncertainty are also discussed for the different aspects addressed.


Assuntos
Guias de Prática Clínica como Assunto , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Progressão da Doença , Humanos , Nefrologia , Sociedades Médicas , Espanha
6.
Nefrologia ; 33(5): 629-39, 2013.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-24089154

RESUMO

INTRODUCTION: A study published in 2011 showed that patients in the Canary Islands, who were incident in peritoneal dialysis (PD) had better survival than those who were incident in hemodialysis (HD). Since initiating hemodialysis with central venous catheter is associated with worse prognosis, it would be possible that the initial vascular access influences the results of survival comparison between both groups. OBJECTIVE: To conduct a comparative medium-term survival study of patients incident in renal replacement therapy with different modalities in our community, classifying those incident in hemodialysis according to the initial vascular access: established arteriovenous vascular access or central venous catheter. MATERIAL AND METHOD: Retrospective longitudinal cohort study including all patients who were incident in renal replacement therapy between January 2005 and December 2010, with follow-up until December 2011, in three large hospitals of the Canary Islands. Patients were classified according to the initial modality: PD, HD with established vascular access (HD-FAV) or HD with central venous catheter (HD-Cat). Kaplan-Meier survival curves were estimated for each group and a Cox proportional hazards survival model was used to estimate relative mortality risk for DP as compared to HD-FAV and HD-Cat, adjusting for age and Charlson comorbidity index. An equivalent analysis was then conducted on subgroups defined by age or by the presence of diabetes. RESULTS: 1110 patients were included, with a median age of 63 years, 56% of them were diabetic. A Kaplan-Meier analysis showed better survival for PD (66 months) as compared to HD-Cat (41 months), Log Rank p<.001, with no difference between DP and HD-FAV (67 months). Cox regression RR of mortality for HD-Cat versus PD was 2.270 (1.573-3.276); p<.001; no differences were found between HD-FAV and PD patients 0.993 (0.646-1.525) n.s. Subgroup analysis showed equivalent results for diabetic and non-diabetic patients as well as for younger or older ones. CONCLUSIONS: better survival of PD patients as compared to HD ones, observed in the Canary Islands, seems to be based on incident HD patients with central venous catheter, while no differences were found between PD and HD with established vascular access. These results could suggest that patients in our community, for whom a vascular access cannot be achieved in predialysis, could have better survival if PD is offered as initial technique, at least until a vascular access is available.


Assuntos
Cateterismo Venoso Central , Diálise Peritoneal/mortalidade , Diálise Renal/mortalidade , Dispositivos de Acesso Vascular , Fatores Etários , Idoso , Comorbidade , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Espanha/epidemiologia
7.
Nefrología (Madr.) ; 33(5): 629-639, oct. 2013. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-117687

RESUMO

INTRODUCCIÓN: En un estudio publicado en 2011 se observó que en la Comunidad Canaria la supervivencia de los pacientes incidentes en diálisis peritoneal (DP) es mejor que la de los pacientes incidentes en hemodiálisis (HD). El inicio de HD con catéter venoso central condiciona un peor pronóstico, por lo que el acceso vascular de inicio podría condicionar la comparación de la supervivencia entre ambas modalidades. OBJETIVO: Realizar un estudio comparativo en nuestra comunidad de la supervivencia a medio plazo de los pacientes incidentes en tratamiento renal sustitutivo según la modalidad, separando a los pacientes incidentes en HD según el acceso vascular de inicio: acceso vascular arteriovenoso desarrollado o catéter venoso central. MATERIAL Y MÉTODOS: Se trata de un estudio de cohortes longitudinal retrospectivo, que incluyó todos los pacientes incidentes en tratamiento renal sustitutivo entre enero de 2005 y diciembre de 2010 seguidos hasta diciembre de 2011 en tres de los grandes hospitales de la Comunidad Canaria y se dividieron, según la modalidad de inicio, en DP, HD con acceso vascular desarrollado (HD-FAV) y HD con catéter venoso central (HD-Cat). Se estimaron las curvas de supervivencia en los distintos grupos mediante Kaplan-Meier y se aplicó un modelo de riesgos proporcionales de Cox de supervivencia para estimar los riesgos relativos de mortalidad de DP, frente a HD-FAV y HD-Cat, ajustando para edad e índice de comorbilidad de Charlson. Posteriormente se realizó el mismo análisis por subgrupos definidos por la edad y presencia de diabetes. RESULTADOS: Se incluyeron 1110 pacientes, mediana de edad 63 años, 56 % diabéticos. El análisis de Kaplan-Meier muestra una mejor supervivencia de DP (66 meses) frente a HD-Cat (41 meses), log-rank p < 0,001, no existiendo diferencia entre DP y HD-FAV (67 meses). En la regresión de Cox el riesgo relativo de mortalidad de la HD-Cat frente a la DP fue de 2,270 (1,573-3,276); p < 0,001. No se observó diferencia entre los pacientes HD-FAV y DP 0,993 (0,646-1,525). El análisis por subgrupos muestra estos mismos resultados en diabéticos y no diabéticos, y en los pacientes más jóvenes y en los más añosos. CONCLUSIONES: La mejor supervivencia en DP frente a HD observada en el registro de enfermos renales de la Comunidad Canaria parece a expensas de los pacientes incidentes en HD-Cat, no observándose diferencia entre DP y HD-FAV. Estos resultados podrían sugerir que, en nuestro medio, aquellos pacientes en los que, optando inicialmente por HD, no se consigue un acceso vascular desarrollado en la etapa prediálisis podrían obtener un beneficio de supervivencia ofreciéndoles la DP como técnica de inicio, al menos hasta disponer de un acceso vascular definitivo


OBJECTIVE: To conduct a comparative medium-term survival study of patients incident in renal replacement therapy with different modalities in our community, classifying those incident in hemodialysis according to the initial vascular access: established arteriovenous vascular access or central venous catheter. MATERIAL AND METHOD: Retrospective longitudinal cohort study including all patients who were incident in renal replacement therapy between January 2005 and December 2010, with follow-up until December 2011, in three large hospitals of the Canary Islands. Patients were classified according to the initial modality: PD, HD with established vascular access (HD-FAV) or HD with central venous catheter (HD-Cat). Kaplan-Meier survival curves were estimated for each group and a Cox proportional hazards survival model was used to estimate relative mortality risk for DP as compared to HD-FAV and HD-Cat, adjusting for age and Charlson comorbidity index. An equivalent analysis was then conducted on subgroups defined by age or by the presence of diabetes. RESULTS: 1110 patients were included, with a median age of 63 years, 56% of them were diabetic. A Kaplan-Meier analysis showed better survival for PD (66 months) as compared to HD-Cat (41 months), Log Rank p<.001, with no difference between DP and HD-FAV (67 months). Cox regression RR of mortality for HD-Cat versus PD was 2.270 (1.573-3.276); p<.001; no differences were found between HD-FAV and PD patients 0.993 (0.646-1.525) n.s. Subgroup analysis showed equivalent results for diabetic and non-diabetic patients as well as for younger or older ones. CONCLUSIONS: better survival of PD patients as compared to HD ones, observed in the Canary Islands, seems to be based on incident HD patients with central venous catheter, while no differences were found between PD and HD with established vascular access. These results could suggest that patients in our community, for whom a vascular access cannot be achieved in predialysis, could have better survival if PD is offered as initial technique, at least until a vascular access is available


Assuntos
Humanos , Diálise Peritoneal , Insuficiência Renal Crônica/terapia , Diálise Renal/tendências , Taxa de Sobrevida/tendências , Cateteres de Demora , Cateterismo Venoso Central , Cateterismo Periférico , Fatores de Risco
8.
Phys Chem Chem Phys ; 15(33): 13940-50, 2013 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-23852406

RESUMO

In this paper we describe a novel combination of Raman spectroscopy, isotope editing and X-ray scattering as a powerful approach to give detailed structural information on aromatic side chains in peptide fibrils. The orientation of the tyrosine residues in fibrils of the peptide YTIAALLSPYS with respect to the fibril axis has been determined from a combination of polarised Raman spectroscopy and X-ray diffraction measurements. The Raman intensity of selected tyrosine bands collected at different polarisation geometries is related to the values and orientation of the Raman tensor for those specific vibrations. Using published Raman tensor values we solved the relevant expressions for both of the two tyrosine residues present in this peptide. Ring deuteration in one of the two tyrosine side chains allowed for the calculation to be performed individually for both, by virtue of the isotopic shift that eliminates band overlapping. Sample disorder was taken into account by obtaining the distribution of orientations of the samples from X-ray diffraction experiments. The results provide previously unavailable details about the molecular conformation of this peptide, and demonstrate the value of this approach for the study of amyloid fibrils.


Assuntos
Peptídeos beta-Amiloides/química , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Deutério/química , Espectroscopia de Ressonância Magnética , Modelos Teóricos , Estrutura Secundária de Proteína , Análise Espectral Raman , Tirosina/química
9.
Case Rep Med ; 2013: 935172, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23762079

RESUMO

Although clinical presentation of fibrillary glomerulonephritis is similar to most forms of glomerulonephritis, it is usually difficult to make the diagnosis. Clinical manifestations include proteinuria, microscopic haematuria, nephrotic syndrome, and impairment of renal function. A diagnosis of fibrillary glomerulonephritis is only confirmed by renal biopsy and it must comprise electronmicroscopy-verified ultrastructural findings. We report four cases between 45-50 years old with documented type 2 diabetes mellitus (T2DM) and arterial hypertension. All patients were found to have fibrils on kidney biopsy. The differential diagnosis of fibrils in the setting of diabetes mellitus is also discussed.

10.
Nefrología (Madr.) ; 33(2): 256-265, mar.-abr. 2013. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-112324

RESUMO

La insuficiencia cardíaca (IC) y el fracaso renal agudo (FRA) son dos entidades muy prevalentes en nuestro medio, e inciden de manera directa y sinérgicamente en la morbimortalidad de nuestros pacientes. Cuando es oligoanúrico, el FRA suele conducir a la sobrecarga hídrica, representando esta el núcleo precipitante del mecanismo de descompensación aguda de la IC, y está asociada con el agravamiento de los síntomas, la hospitalización y la muerte. Determinar el balance hídrico en la IC puede ser complejo y depende, en gran medida, de la fisiopatología subyacente. Los nuevos biomarcadores y las nuevas tecnologías están demostrando ser útiles para la detección e identificación de riesgo de IC descompensada aguda que puede permitir una pronta intervención y reversión del FRA que se traduzca en mejores resultados clínicos (AU)


Heart failure (HF) and acute renal failure (ARF) are two very prevalent entities in our environment which impact directly and synergistically in the morbidity and mortality of our patients. ARF, when oligoanuric, often leads to water overload. It represents the precipitating core of the mechanism of acute decompensation of the HF and is associated with the worsening of symptoms, hospitalisation and death. Determining the water balance in HF can be complex and depends, largely, on the underlying pathophysiology. New biomarkers and new technologies are proving to be useful for the detection and identification of risk of acutely decompensated HF that may allow early intervention and reversal of the ARF that translates into better clinical outcomes (AU)


Assuntos
Humanos , Insuficiência Cardíaca/fisiopatologia , Injúria Renal Aguda/fisiopatologia , Desequilíbrio Hidroeletrolítico/etiologia , Biomarcadores/análise , Fatores de Risco
11.
Nefrologia ; 33(2): 256-65, 2013.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-23364578

RESUMO

Heart failure (HF) and acute renal failure (ARF) are two very prevalent entities in our environment which impact directly and synergistically in the morbidity and mortality of our patients. ARF, when oligoanuric, often leads to water overload. It represents the precipitating core of the mechanism of acute decompensation of the HF and is associated with the worsening of symptoms, hospitalisation and death. Determining the water balance in HF can be complex and depends, largely, on the underlying pathophysiology. New biomarkers and new technologies are proving to be useful for the detection and identification of risk of acutely decompensated HF that may allow early intervention and reversal of the ARF that translates into better clinical outcomes.


Assuntos
Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Água/metabolismo , Biomarcadores , Humanos
12.
Nefrología (Madr.) ; 32(5): 573-578, sept.-oct. 2012. ilus
Artigo em Espanhol | IBECS | ID: ibc-106146

RESUMO

El 4-10% de los pacientes incidentes en diálisis portan un injerto renal no funcionante y hasta en el 32% de los casos, según las series, se requiere la realización de trasplantectomía por diversas causas. La mortalidad de estos pacientes es significativamente mayor que la de aquéllos con injerto funcionante o en terapia renal sustitutiva sin injerto previo. Se han sugerido como indicaciones actuales de trasplantectomía el síndrome de intolerancia al injerto, la pérdida precoz de éste, la presencia de proteinuria grave, pielonefritis recurrentes o neoplasia y el síndrome de inflamación crónica. El síndrome de inflamación crónica se presenta en enfermos con elevación de los marcadores de inflamación (proteína C reactiva), anemia con resistencia al tratamiento con estimuladores de la eritropoyesis y marcadores de desnutrición en su contexto. Esta situación de inflamación está provocada por el injerto y revierte tras la trasplantectomía, como han demostrado varios estudios. Hemos revisado la literatura publicada al respecto, las indicaciones de trasplantectomía, o embolectomía, sus ventajas e inconvenientes; la incidencia del síndrome de intolerancia al injerto y la fisiopatología del síndrome de inflamación crónica, así como el algoritmo de manejo terapéutico propuesto actualmente (AU)


Approximately 4%-10% of incident patients on dialysis have a non-functioning kidney graft, and according to series, as many as 32% require transplantectomy for a variety of reasons. Mortality in these patients is significantly higher than in those with a functioning graft or on renal replacement therapy without having received a graft. Graft intolerance syndrome, early graft loss, severe proteinuria, recurring pyelonephritis or neoplasia, and chronic inflammation syndrome have all been proposed as indications for transplantectomy. Chronic inflammation syndrome occurs in patients with high levels of inflammatory markers (C-reactive protein), anaemia resistant to treatment with erythropoiesis stimulators, and malnutrition markers. This inflammatory state is provoked by the graft, and reverts when a transplantectomy is performed, as several studies have shown. We have reviewed the medical literature published on this topic, the indications for transplantectomy and embolectomy, their advantages and disadvantages, the incidence of graft intolerance syndrome, and the pathophysiology of chronic inflammation syndrome, as well as the currently proposed therapeutic management algorithm (AU)


Assuntos
Humanos , Nefrectomia , Transplante de Rim/efeitos adversos , Rejeição de Enxerto/cirurgia , Embolização Terapêutica , Síndrome de Resposta Inflamatória Sistêmica/complicações
13.
Chem Commun (Camb) ; 48(97): 11835-7, 2012 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-22950086

RESUMO

A novel combination of site-specific isotope labelling, polarised infrared spectroscopy and molecular combing reveals local orientational ordering in the fibril-forming peptide YTIAALLSPYSGGRADS. Use of (13)C-(18)O labelled alanine residues demonstrates that the N-terminal end of the peptide is incorporated into the cross-beta structure, while the C-terminal end shows orientational disorder.


Assuntos
Oligopeptídeos/química , Alanina/química , Isótopos de Carbono , Marcação por Isótopo , Modelos Moleculares , Isótopos de Oxigênio , Espectroscopia de Infravermelho com Transformada de Fourier
14.
Nefrologia ; 32(5): 573-8, 2012.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-23013942

RESUMO

Approximately 4%-10% of incident patients on dialysis have a non-functioning kidney graft, and according to series, as many as 32% require transplantectomy for a variety of reasons. Mortality in these patients is significantly higher than in those with a functioning graft or on renal replacement therapy without having received a graft. Graft intolerance syndrome, early graft loss, severe proteinuria, recurring pyelonephritis or neoplasia, and chronic inflammation syndrome have all been proposed as indications for transplantectomy. Chronic inflammation syndrome occurs in patients with high levels of inflammatory markers (C-reactive protein), anaemia resistant to treatment with erythropoiesis stimulators, and malnutrition markers. This inflammatory state is provoked by the graft, and reverts when a transplantectomy is performed, as several studies have shown. We have reviewed the medical literature published on this topic, the indications for transplantectomy and embolectomy, their advantages and disadvantages, the incidence of graft intolerance syndrome, and the pathophysiology of chronic inflammation syndrome, as well as the currently proposed therapeutic management algorithm.


Assuntos
Transplante de Rim , Nefrectomia , Complicações Pós-Operatórias/cirurgia , Insuficiência Renal/cirurgia , Humanos , Transplante de Rim/imunologia , Insuficiência Renal/imunologia
15.
Mol Cell Biochem ; 369(1-2): 235-46, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22798153

RESUMO

The resistance of internal mammary artery (IMA) toward atherosclerosis is not well understood. In plasma, homocysteine (Hcy) occurs in reduced, oxidized, homocysteine thiolactone and a component of proteins as a result of N- or S-homocysteinylation. We evaluated S/N-homocysteinylated protein levels in IMA fragments of patients undergoing coronary artery bypass grafting, and whether they were affected by genetic common variants. We tested whether tHcy, Hcy-S-protein levels, genotypes or Hcy-induced methylation modifications were related to differences in iNOS, Ddah2, and eNOS gene expression between territories. A small percentage of Hcy-S-proteins were found in IMA fragments. The Mthfr C677T (rs1801133) and Pon-1 Leu55Met (rs854560) variants were associated with Hcy-S-proteins. We observed a gradual difference according to Hcy-S-protein levels in the methylation degree of the Ddah2 gene promoter in aortic, but not in IMA, fragments. No correlation between the degree of methylation and the Ddah2 gene expression levels was found in both types of analyzed fragments. Total Hcy but not Hcy-S-proteins correlated with iNOS promoter methylation. Analyzed variants seem to contribute to the in vivo Hcy binding properties to IMA. The contribution of the Hcy-derived methylation modifications to Ddah2 and eNOS gene expression seems to be tissue-specific and independent of the Ddah2/ADMA/eNOS pathway. Hcy-derived methylation modifications to the iNOS gene promoter contribute to a lesser extent to iNOS gene expression.


Assuntos
Aorta/enzimologia , Aterosclerose , Homocisteína , Artéria Torácica Interna/enzimologia , Idoso , Amidoidrolases/genética , Amidoidrolases/metabolismo , Aterosclerose/enzimologia , Aterosclerose/genética , Ponte de Artéria Coronária , Feminino , Expressão Gênica , Genótipo , Homocisteína/genética , Homocisteína/metabolismo , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Polimorfismo Genético , Regiões Promotoras Genéticas
17.
Clin Invest Med ; 35(2): E55-64, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22469105

RESUMO

PURPOSE: Telmisartan, an angiotensin II receptor blocker (ARB), also acts as an activator of peroxisome proliferator-activated receptor-gamma (PPAR-gamma; PPAR-γ). Several studies have explored the PPAR-γ-endothelial nitric oxide synthase (eNOS) pathway associated with improvement of endothelial function by telmisartan. The ability of telmisartan to induce gene expression and protein level of eNOS and PPARγ in adipocytes was investigated. METHODS: Expression of aP2, PPARγ, eNOS and iNOS genes were measured using the quantitative real-time polymerase chain reaction. The changes, at the protein level, were explored by Western blot, which evaluated the native and phosphorylated eNOS forms, eNOS-Ser(1177) and eNOS-Thr(495). RESULTS: Adipocytes, exposed to telmisartan, exhibited an increase in PPARγ gene expression but a decrease in protein level. Nonetheless, after the exposure to telmisartan, eNOS-Ser(1177) phosphorylation, associated with eNOS activity increment, reached its highest value while eNOS-Thr(495) phosphorylation, involved in the inhibition of eNOS activity, showed its lowest value. CONCLUSION: The results suggest that telmisartan preserves eNOS activity via a mechanism that is partially independent of the PPARγ-eNOS pathway in adipocytes.


Assuntos
Benzimidazóis/farmacologia , Benzoatos/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , PPAR gama/agonistas , Células 3T3 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Western Blotting , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Camundongos , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Nitritos/metabolismo , PPAR gama/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Telmisartan
19.
Nephrol Dial Transplant ; 27(7): 2720-33, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22302208

RESUMO

BACKGROUND: Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease. METHODS: Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys. RESULTS: In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries. CONCLUSIONS: In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Nefropatias/etiologia , Nefropatias/prevenção & controle , Losartan/uso terapêutico , Nefrectomia/efeitos adversos , Piridinas/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/antagonistas & inibidores , Animais , Western Blotting , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Quimioterapia Combinada , Fibronectinas/genética , Fibronectinas/metabolismo , Nefropatias/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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