Asociación del polimorfismo rs5186 del gen AGTR1 con disminución de la TFGe en pacientes con diabetes tipo 2 de la Ciudad de México / Association of the rs5186 polymorphism of the AGTR1 gene with decreased eGFR in patients with type 2 diabetes from Mexico City

Antecedentes: La búsqueda de biomarcadores tempranos de enfermedad renal diabética (ERD) en pacientes con diabetes mellitus tipo 2 (DMT2), como los marcadores genéticos para identificar pacientes vulnerables de la enfermedad, incluso antes de la presencia de una disminución de la estimación de tasa de filtrado glomerular (TFGe) o presencia de microalbuminuria ha cobrado importancia en los últimos años. El polimorfismo rs5186 (A1166C) presente en el gen receptor tipo 1 de la angiotensina II (AGTR1) ha sido asociado a distintos efectos del riesgo de daño renal que suelen estar presentes en pacientes con diabetes mellitus (DM). Se ha descrito que el rs5186 podría influir en la estabilidad de las proteínas que conforman al receptor de la angiotensina II tipo 1 (AT1) alterando su actividad, por lo que podría ser considerado como un factor de riesgo a enfermedad renal crónica (ERC) caracterizada por una disminución progresiva de la TFG. Sin embargo, la asociación del polimorfismo rs5186 del gen AGTR1 con ERD en pacientes con DMT2 ha sido controversial, no concluyente, incluso nula. Las controversias podrían ser por los estudios de asociación y estimación del riesgo del rs5186 previamente reportados incluyen distintos fenotipos clínicos considerados como inductores y potenciadores de ERC, además, los tamaños de las muestras analizadas en pacientes con DMT2 eran pequeñas y no tenían un control estricto en su inclusión, careciendo incluso de marcadores bioquímicos o estadificación KDOQI que han dificultado su análisis. Objetivo: Determinar la asociación del rs5186 del gen AGTR1 con la disminución de TFGe considerada como riesgo al desarrollo de ERD en pacientes con DMT2.(AU)

Background: Early biomarkers search for Diabetic Kidney Disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM), as genetic markers to identify vulnerable carriers of the disease even before Glomerular Filtration Rate (GFR) decline or microalbuminuria development, has been relevant during the last few years. The rs5186 (A116C) polymorphism of the Angiotensin II Receptor Type I gene (AGTR1), has been associated to multiple effects of renal injury risk, commonly detected in patients with Diabetes Mellitus (DM). It has been described that rs5186 could have an effect in stability proteins that assemble Angiotensin II Receptor Type I (AT1), modifying its action, which is why it should be considered as a risk factor for Chronic Kidney Disease (CKD), characterized by a GFR progressive reduction. Even though, the association between rs5186 AGTR1 gene polymorphism and DKD in patients with T2DM has been controversial, inconclusive, and even absent. This disputable issue might be as a result of association studies in which many and varied clinical phenotypes included are contemplated as CKD inductors and enhancers. Although, the sample sizes studied in patients with T2DM are undersized and did not have a strict inclusion criteria, lacking of biochemical markers or KDOQI classification, which have hindered its examination.Objective: The aim of our study was to establish an association between rs5186 AGTR1 gene polymorphism and GFR depletion, assessed as a risk factor to DKD development in patients with T2DM. (AU)

Aging modifies receptor expression but not muscular contractile response to angiotensin II in rat jejunum

The involvement of renin-angiotensin system in the modulation of gut motility and age-related changes in mRNA expression of angiotensin (Ang II) receptors (ATR) are well accepted. We aimed to characterize, in vitro, the contractile responses induced by Ang II, in jejunum from young (3–6 weeks old) and old rats (≥ 1 year old), to evaluate possible functional differences associated to changes in receptor expression. Mechanical responses to Ang II were examined in vitro as changes in isometric tension. ATR expression was assessed by qRT-PCR. Ang II induced a contractile effect, antagonized by losartan, AT1R antagonist, and increased by PD123319, AT2R antagonist, as well by neural blocker ω-conotoxin and by nitric oxide (NO) synthase inhibitor. No difference in the response was observed between young and old groups. AT1 receptor-mediated contractile response was decreased by U-73122, phospholipase C (PLC) inhibitor; or 2-aminoethoxy-diphenylborate (2-APB), inositol triphosphate (IP3) receptor inhibitor; or nifedipine, L-type calcium channel blocker. Age-related changes in the expression of both AT1 receptor subtypes, AT1a and AT1b, and of AT2 receptors were detected. In conclusion, Ang II modulates the spontaneous contractility of rat jejunum via postjunctional AT1 receptors, involving Ca2+ mobilization from intracellular stores, via PLC/IP3 pathway, and Ca2+ influx from extracellular space, via L-type channels. Prejunctional AT2 receptors would counteract AT1 receptor effects, via NO synthesis. The observed age-related differences in the expression of all AT receptor subtypes are not reflected in the muscular contractile response to Ang II. (AU)

Angiotensin 2 type 1 receptor blockade different affects postishemic kidney injury in normotensive and hypertensive rats

Many studies demonstrated that angiotensin 2 type 1 receptor (AT1R) blockade accelerates renal recovery in post-ischaemic kidney but there are many controversies related to its net effect on kidney structure and function. During the past years, our research group was trying to define the pathophysiological significance of the renin-angiotensin system on post-ischemic acute renal failure (ARF) development in normotensive Wistar as well as hypertensive rats (SHR). This review mostly summarizes our experience in that field. Our previous studies in normotensive rats revealed that AT1R blockade, except slightly renal vascular resistance improvement, had no other obvious beneficial effects, and therefore implies angiotensin 2 (Ang-2) overexpression as non-dominant on kidney reperfusion injuries development. Similarly it was observed in Wistar rats with induced mild (L-NAME, 3 mg/kg b.w.) nitric oxide (NO) deficiency. Expectably, in strong induced (L-NAME, 10 mg/kg b.w.) NO deficiency associated with ARF, massive tubular injuries indicate harmful effects of AT1R blockade, implying strongly disturbed glomerular filtration and suggesting special precaution related to AT1R blockers usage. Opposite to previous, by our opinion, AT1R antagonism promises new advance in treatment of essentially hypertensive subjects who develop ARF. Increased glomerular filtration, diminished oxidative stress, and most importantly improved tubular structure in postishemic SHR treated with AT1R blocker losartan, implicate Ang-2 over production as potently agent in the kidney ischemic injury, partly trough generation of reactive oxygen species. These data contribute understanding the pathogenesis of this devastating illness in hypertensive surroundings (AU)

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A common effect of angiotensin II and relaxin 2 on the PNT1A normal prostate epithelial cell line

The prostate gland is a part of the male reproductive tract which produces both angiotensin II (Ang II) and relaxin 2 (RLN2). The present study analyzes the effect of both these peptide hormones at concentration 10−8M on viability, proliferation, adhesion, migration, and invasion of normal prostate epithelial cells (PNT1A). Improved survival in two- and three-dimensional cell cultures was noted as well as visual changes in colony size and structure in Geltrex™. Stimulatory influence on cell viability of each peptide applied single was lower than in combination. Enhanced survival of PNT1A cells appears to be associated with increased BCL2/BAX messenger RNA (mRNA) expression ratio. Modulation of cell spreading and cell-extracellular matrix adhesion dynamics were also altered as an influence of tested hormone application. However, long-term Ang II and RLN2 effects may lead to an increase of normal prostate cell migration and invasion abilities. Moreover, gelatin zymography revealed that both gelatinases A and B were augmented by Ang II treatment, whereas RLN2 significantly stimulated only MMP-9 secretion. These results support the hypothesis that deregulation of locally secreted peptide hormones such as Ang II and RLN2 may take part in the development of certain cancers, including prostate cancer. Moreover, the observed ability of relaxin 2 to act as a regulator of mRNA expression levels not only LGR7 but also classic angiotensin receptors suggested that renin-angiotensin system and relaxin family peptide system are functionally linked (AU)

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Plasminogen activator inhibitor-1 and angiotensin converting enzyme gene polymorphisms in Turkish asthmatic children

Background: Polymorphisms of plasminogen activator inhibitor-1 (PAI-1) and angiotensin-converting enzyme (ACE) genes have been implicated in susceptibility to asthma. In this study, we aimed to investigate whether there was any association between childhood asthma and polymorphisms of the PAI-1 and ACE genes. Methods: Two hundred and three Turkish children aged 5–15 years, including 102 asthmatic patients and 101 healthy control subjects were included in this study. The asthma group was divided into two groups as follows: Group I: Asthmatic children with positive family history for atopy (n=53), Group II: Asthmatic children without any family history for atopy (n=49). One hundred and twenty-eight atopic family members were also included in the study. The insertion/deletion (I/D) polymorphism of the ACE and PAI-1 4G/5G gene polymorphisms was carried out by polymerase chain reaction. Results: The prevalence of the PAI-1 4G allele was significantly greater in asthmatic children compared to control group (p<0.05, OR: 1.64 (1.11–2.43)) but there was no significant relation between ACE I/D genotypes and childhood asthma. No significant difference was detected between Groups I and II in terms of these ACE and PAI-1 genotypes and allele frequencies. No significant relationship was found between both gene polymorphisms and total serum IgE and skin prick test results. Conclusion: It has been established that PAI-1 4G allele may be a genetic risk factor for childhood asthma but ACE gene I/D polymorphisms do not play a role in the development of asthma in the sample of Turkish children(AU)

Bloqueo neurohormonal al alta en pacientes con insuficiencia cardiaca / Neurohormonal blockade in patients with heart failure at discharge from hospital

Con el objetivo de valorar el grado de cumplimiento del tratamiento farmacológico en pacientes con ICC se diseñó el estudio de adherencia terapéutica en insuficiencia cardiaca (ATICA). Durante el periodo de inclusión se han obtenido datos demográficos, sociales, educacionales, antecedentes personales, exploración física y analítica de los pacientes. Estos datos mencionados son los que se reflejan en el presente estudio piloto. El total de pacientes incluidos es de 586, la mayoría de los cuales son mujeres, la edad media es avanzada y presentan una fracción de eyección conservada en más de la mitad. Respecto al esquema terapéutico únicamente se recogió información de grupos con acción neurohormonal y de reconocimiento en el tratamiento de la ICC. El grupo farmacológico más utilizado son los IECA, sin embargo fármacos como la espirolactona o los BB, siguen mostrando un grado de infrautilización preocupante, aunque presentan una prescripción mayor que en otras series

With the objective to value the degree of fulfillment of the pharmacological processing in patients with heart failure was designed the study of therapeutic adherence in heart failure (ATICA). During the period of inclusion educational, social, demographic data have been obtained, personal antecedents, analytic and physical exploration of the patients. These data mentioned are the ones that are reflected in the present pilot study. The total of patients included is 554, the majority of which are women, the middle ages is advanced and they present a fraction of eyección conserved in more than the half. In the therapeutic plan only was collected information of groups with neurohormonal action and of great recognition in the processing of the heart failure. The most utilized pharmacological group are the IECA, nevertheless medicines as the espirolactona or the betablocker continue showing a worrying degree of infrautilización, although they present a greater prescription that in other series

Efecto de dos combinaciones antihipertensivas sobre la presión arterial, albuminuria y control glucémico en pacientes con nefropatía diabética tipo 2: un estudio aleatorizado / Effect of two different antihypertensive drug combinations over blodd pressure, albuminuria and glycemic control in patients with diabetic nephropathy type II

Los pacientes diabéticos tipo 2 con albuminuria presentan un elevado riesgo de complicaciones cardiovasculares; el intenso tratamiento antihipertensivo que precisan implica con frecuencia el uso de combinaciones. El objetivo del presente estudio fue comparar el efecto de dos diferentes combinaciones, basadas en el bloqueo del sistema renina-angiotensina, sobre la PA, albuminuria y control glucémico. El diseño fue prospectivo, aleatorizado, de ramas paralelas, controlado y llevado a cabo en un único Servicio de Endocrinología, en España. Se incluyeron 77 diabéticos tipo 2 con albuminuria estable entre 30 y 1.000 mg/día. Tras un período de pre-inclusión de dos semanas, las pacientes fueron aleatorizados a verapamil SR/trandolapril 180/2 (VT) o losartan/hidroclorotiazida (LH) 20/12,5 mg/día. La duración del tratamiento fue un año. Los parámetros evaluados fueron los cambios en la presión arterial, excreción urinaria de albúmina (24 horas), hemoglobina glicosilada y urea plasmática. La PA global descendió significativamente de 161,6 ñ 18,7 / 83,6 ñ 10,2 mmHg a 137,2 ñ 15,7 / 70,9 ñ 8,3 mmHg (p < 0,0005). Por tratamientos, los valores fueron: Para VT, 164,3 ñ 18,5 / 87,2 ñ 10,7 mmHg inicial y 135,0 ñ 15,1 / 71,3 ñ 8,4 mmHg final. Para LH, 158,8 ñ 17,4 / 80,1ñ 8,4 mmHg inicial y 139,3 ñ 16,1 / 70,5 ñ 8,2 mm Hg final. La albuminuria se redujo significativamente de 308,2 ñ 544,7 mg/día a 198,0 ñ 285,3 mg/día; en ambos parámetros sin diferencias significativas entre tratamientos. La hemoglobina glicosilada descendió de 7,59 ñ 1,30 por ciento a 7,14 ñ 1,20 por ciento en el grupo VT y de 7,96 ñ 1,29 por ciento a 7,84 ñ 1,62 por ciento en el grupo LH (ANOVA, p = 0,022).Los cambios ajustados por los valores basales alcanzaron diferencias casi significativas entre tratamientos (p = 0,092). La urea plasmática pasó de 39,8 ñ 12,7 mg/dL a 40,5 ñ 11,1 mg/dL en el grupo TV y de 43,4 ñ 12,0 mg/dL a 52,4 ñ 19,4 mg/dL en el grupo LH (ANOVA, p = 0,028). En conclusión, en NEFROLOGÍA. Vol. XXII. Número 2. 2002 pacientes diabéticos tipo 2 con albuminuria estable, ambos tratamientos reducen la presión arterial y la albuminuria de forma similar. La combinación verapamil/trandolapril contribuye mejor al control metabólico hidrocarbonado que losartan/hidroclorotiazida (AU)

Acción hipouricemiante de Losartan® en el trasplante renal

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