RESUMEN
BACKGROUND: Low-density lipoprotein apheresis is not specific to lipoproteins but removes immunoglobulins as well. It remains elusive, whether protective SARS-CoV-2 antibodies after vaccination from COVID-19 are eliminated as well. METHODS: A cross-sectional case-control study on 55 patients undergoing weekly lipoprotein apheresis and 21 patients with comparable comorbidities and epidemiology not undergoing apheresis. SARS-CoV-2 IgG was assessed in all patients prior to apheresis and in 38 patients both before and after apheresis. RESULTS: SARS-CoV-2 IgG concentrations before a session of lipoprotein apheresis were comparable to control patients not undergoing apheresis(1727 IU/ml, IQR 365-2500) vs. 1652 IU/ml,(IQR408.8-2500), p = 0.78). SARS-CoV-2 IgG concentrations were reduced by lipoprotein apheresis from 1656 IU/ml(IQR 540.5-2500) prior to 1305 IU/ml (IQR 449-2500) afterwards(p < 0.0001). CONCLUSION: Lipoprotein apheresis removes SARS-CoV-2 IgG. The average elimination rate was 21.2%. In the present population of patients undergoing apheresis once weekly, however, the elimination did not lead to inferior concentrations compared to patients not undergoing lipoprotein apheresis.
Asunto(s)
Eliminación de Componentes Sanguíneos , COVID-19 , Humanos , SARS-CoV-2 , Estudios de Casos y Controles , Estudios Transversales , COVID-19/terapia , Lipoproteínas , Lipoproteínas LDL , Inmunoglobulina GRESUMEN
INTRODUCTION: In the general population, hyperuricemia is associated with increased morbidity and mortality. Data on this association in hemodialysis patients is controversial. Moreover, it remains elusive whether serum uric acid (SUA) lowering therapy is associated with mortality. METHODS: Retrospective analysis of 601 patients on chronic hemodialysis therapy in five outpatient centers with a maximum follow-up of 100 and a mean follow-up of 41 months. Death was defined as primary endpoint. Cumulative survival was analyzed by Kaplan-Meier analysis and Cox regressions adjusted for age. FINDINGS: Cumulative survival rates were higher for those subjects with a higher than median SUA concentration both based on mean annual and baseline measurements (p < 0.05 each). There was no survival difference anymore after adjustment for age (p > 0.05 each). Stratification for SUA lowering therapy (allopurinol/febuxostat) had no impact on cumulative survival, neither in Kaplan Meier nor in Cox regression analyses (p > 0.05 each). Furthermore, Cox regression analysis excluded an increased cardiovascular mortality in subjects with hyperuricemia. DISCUSSION: In contrast to the general population, hyperuricemia is not associated with increased mortality in patients undergoing hemodialysis. Moreover, xanthine oxidase inhibition was not associated with a survival benefit in this analysis. These data do not support the use of SUA lowering medication in hemodialysis patients with asymptomatic hyperuricemia.
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Gota/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Diálisis Renal , Insuficiencia Renal Crónica/mortalidad , Ácido Úrico/sangre , Anciano , Anciano de 80 o más Años , Alopurinol/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Febuxostat/uso terapéutico , Femenino , Alemania/epidemiología , Gota/sangre , Supresores de la Gota/uso terapéutico , Humanos , Hiperuricemia/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/terapia , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.
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Hígado Graso/genética , Impresión Genómica , Óxido Nítrico Sintasa de Tipo III/genética , Fenotipo , Animales , Metabolismo de los Hidratos de Carbono , Metilación de ADN , Hígado Graso/patología , Femenino , Heterocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/deficiencia , Factores SexualesRESUMEN
BACKGROUND/AIMS: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. METHODS: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. RESULTS: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpine1, TIMP1, Col1a1, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. CONCLUSION: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in ß-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels).
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Endotelina-1/metabolismo , Riñón/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Albúminas/análisis , Animales , Presión Sanguínea , Carnitina/sangre , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Cistatina C/sangre , Endotelina-1/genética , Proteína 3 de Unión a Ácidos Grasos , Proteínas de Unión a Ácidos Grasos/sangre , Proteínas de Unión a Ácidos Grasos/orina , Femenino , Humanos , Riñón/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Mitocondrias/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Osteopontina/sangre , Osteopontina/orina , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
BACKGROUND: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. METHODS: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. RESULTS: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. CONCLUSIONS: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.
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Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Purinas/uso terapéutico , Quinazolinas/uso terapéutico , Xantinas/uso terapéutico , Animales , Dipeptidil Peptidasa 4/fisiología , Inhibidores de la Dipeptidil-Peptidasa IV/química , Linagliptina , Masculino , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Purinas/química , Quinazolinas/química , Distribución Aleatoria , Ratas , Ratas Wistar , Xantinas/químicaRESUMEN
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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Peso al Nacer/genética , Estatura/genética , Desarrollo Fetal/genética , Ligamiento Genético , Sitios de Carácter Cuantitativo , Adulto , Presión Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Recién Nacido , Masculino , Metaanálisis como Asunto , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of insulin resistance and type 2 diabetes in the general population. The RAAS is activated during pregnancy. However, it is unknown whether the RAAS contributes to glycemia in pregnant women. METHODS: Plasma renin activity (PRA) and plasma aldosterone levels were quantified at delivery in 689 Chinese mothers. An oral glucose tolerance test in fasted women was performed in the second trimester of pregnancy. The diagnosis of gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy were made according to the guidelines of the Chinese Society of Obstetrics. RESULTS: Plasma aldosterone was significantly higher in pregnant women with GDM as compared to those without impairment of glycemic control (normal pregnancies: 0.27 +/- 0.21 ng/mL, GDM: 0.36 +/- 0.30 ng/mL; p < 0.05). Regression analyses revealed that PRA was negatively correlated with fasting blood glucose (FBG) (R2 = 0.03, p = 0.007), whereas plasma aldosterone and aldosterone/PRA ratio were positively correlated with FBG (R2 = 0.05, p < 0.001 and R = 0.03, p = 0.007, respectively). Multivariable regression analysis models considering relevant confounding factors confirmed these findings. CONCLUSIONS: This study demonstrated that fasting blood glucose in pregnant women is inversely correlated with the PRA, whereas plasma aldosterone showed a highly significant positive correlation with fasting blood glucose during pregnancy. Moreover, plasma aldosterone is significantly higher in pregnant women with GDM as compared to those women with normal glucose tolerance during pregnancy. Although causality cannot be proven in association studies, these data may indicate that the RAAS during pregnancy contributes to the pathogenesis of insulin resistance/new onset of diabetes during pregnancy.
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Aldosterona/sangre , Glucemia/metabolismo , Diabetes Gestacional/sangre , Hiperglucemia/diagnóstico , Sistema Renina-Angiotensina/fisiología , Renina/sangre , Adulto , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hiperglucemia/sangre , Resistencia a la Insulina/fisiología , Embarazo , Segundo Trimestre del EmbarazoRESUMEN
Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V(1393)I, K(1584)E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V(1393)I) and TRPM6(K(1584)E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T(1391)) and TRPM6(S(1583)). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V(1393)I) and TRPM6(K(1584)E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V(1393)I) and TRPM6(K(1584)E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
Asunto(s)
Diabetes Gestacional/metabolismo , Regulación de la Expresión Génica , Glucosa/metabolismo , Insulina/metabolismo , Canales Catiónicos TRPM/fisiología , Línea Celular , Citoesqueleto/metabolismo , Femenino , Variación Genética , Genotipo , Células HEK293 , Humanos , Riñón/metabolismo , Microscopía Fluorescente/métodos , Modelos Biológicos , Técnicas de Placa-Clamp , Fosforilación , Embarazo , Transducción de Señal , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Canales Catiónicos TRPM/genéticaRESUMEN
BACKGROUND: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT1) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth. METHODS: A genetic association study was conducted at the obstetrics department of the Charité University Hospital, Berlin, Germany. 1191 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy. RESULTS: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin. CONCLUSIONS: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.
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Peso al Nacer/fisiología , Transportador de Glucosa de Tipo 1/genética , Hemoglobina Glucada/metabolismo , Recién Nacido/sangre , Adulto , Femenino , Humanos , Masculino , Parto/sangre , Polimorfismo de Nucleótido Simple , Embarazo/sangreRESUMEN
BACKGROUND: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. METHODS: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. RESULTS: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67% mortality in vehicle-treated rats, but only 20% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). CONCLUSIONS: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.
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Lesión Renal Aguda/tratamiento farmacológico , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Fallo Renal Crónico/tratamiento farmacológico , Metaloendopeptidasas/antagonistas & inhibidores , Neprilisina/antagonistas & inhibidores , Daño por Reperfusión/tratamiento farmacológico , Lesión Renal Aguda/etiología , Albuminuria/etiología , Albuminuria/prevención & control , Animales , Constricción , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Enzimas Convertidoras de Endotelina , Inhibidores Enzimáticos/farmacología , Glomeruloesclerosis Focal y Segmentaria/etiología , Hipertensión/inducido químicamente , Hipertensión/complicaciones , Riñón/irrigación sanguínea , Fallo Renal Crónico/etiología , Masculino , NG-Nitroarginina Metil Éster/toxicidad , Nefrectomía , Ratas , Ratas Wistar , Daño por Reperfusión/complicacionesRESUMEN
OBJECTIVE: To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life. METHOD AND RESULTS: Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancy-induced hypertension revealed that fetal GSP was inversely associated with birth weight (R² = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R² = 0.285; P = 0.010 and R² = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain. CONCLUSION: The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.
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Abdomen , Proteínas Sanguíneas/metabolismo , Cefalometría , Recién Nacido de Bajo Peso , Adulto , Estudios de Cohortes , Femenino , Glicosilación , Humanos , Recién Nacido , Persona de Mediana Edad , EmbarazoRESUMEN
Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5%, p<0.05), especially in those receiving furosemide (-41.9%, p<0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p<0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A1/uso terapéutico , Riñón/efectos de los fármacos , Cirrosis Hepática Experimental/tratamiento farmacológico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptor de Adenosina A1/metabolismo , Animales , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Immunoblotting , Estimación de Kaplan-Meier , Riñón/fisiopatología , Pruebas de Función Renal , Cirrosis Hepática Experimental/sangre , Cirrosis Hepática Experimental/fisiopatología , Cirrosis Hepática Experimental/orina , Masculino , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Ratas , Ratas Wistar , TioacetamidaRESUMEN
UNLABELLED: HYPOTHESIS/ INTRODUCTION: : We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism. MATERIAL AND METHODS: : One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done. RESULTS: : Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 ± 0.70% vs. 6.21 ± 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 ± 0.80%) compared to II mothers delivering boys (6.21 ± 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension. CONCLUSIONS: : Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.
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Glucemia/genética , Mutación INDEL/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Procesos de Determinación del Sexo , Adulto , Femenino , Feto/fisiología , Técnicas de Genotipaje , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Embarazo , Población Blanca/genéticaRESUMEN
Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by ≤46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media:lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-ß1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-ß1 expression.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Cardiomegalia/prevención & control , Inhibidores Enzimáticos/uso terapéutico , Corazón/efectos de los fármacos , Hipertensión Renovascular/tratamiento farmacológico , Metaloendopeptidasas/antagonistas & inhibidores , Neprilisina/antagonistas & inhibidores , Análisis de Varianza , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Relación Dosis-Respuesta a Droga , Enzimas Convertidoras de Endotelina , Inhibidores Enzimáticos/farmacología , Corazón/fisiopatología , Hipertensión Renovascular/complicaciones , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/fisiopatología , Inmunohistoquímica , Losartán/farmacología , Losartán/uso terapéutico , Masculino , Miocardio/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects. METHODS: Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions. RESULTS: The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm(3) respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core. CONCLUSIONS: Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further.
Asunto(s)
Amidas/farmacología , Angiotensinógeno/fisiología , Fumaratos/farmacología , Renina/fisiología , Accidente Cerebrovascular/tratamiento farmacológico , Angiotensinógeno/antagonistas & inhibidores , Angiotensinógeno/genética , Animales , Animales Modificados Genéticamente , Antihipertensivos/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/fisiopatología , Enfermedades Arteriales Cerebrales/fisiopatología , Trastornos Cerebrovasculares/fisiopatología , Quimiocina CXCL1/genética , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-6/genética , Ratas , Renina/antagonistas & inhibidores , Renina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/fisiopatología , Tetrazoles/farmacología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: Transient tachypnea of the newborn (TTN) is the most common perinatal respiratory disorder. It was suggested that the pathogenesis of TTN might involve altered activity of female sex hormones. This study analyzed whether the PROGINS progesterone receptor polymorphism, which is less responsive to progesterone, is associated with TTN. METHODS: A cohort of 2352 infants born to Caucasian women at the Obstetrics Department of the Charite was investigated prospectively. The collected information included the occurrence of respiratory disorders, birth weight, gestational age at delivery, mode of delivery, and maternal morbidity. Mothers and newborns were genotyped for the PROGINS progesterone receptor polymorphism. Statistical analyses considered correction for confounding factors. RESULTS: The presence of the mutated T2-allele either in mothers or in infants was associated with a reduction of the incidence of TTN in a gene dose-dependent manner (mothers T1/T1: 6.6%, T1/T2: 4.3% T2/T2: 2.3%, p < 0.01; infants T1/T1: 6.5%, T1/T2: 4.7%, T2/T2: 0.0%, p = 0.02 in a multivariable regression model). The total number of mutated T2-alleles present in a mother/child pair was associated with a reduction of TTN (4 T2-alleles: 6.4%, n=95; 3: 5.9%, n=30; 2: 3.1%, n=9; 1: 1.4%, n=1; 0:0%, n=0; p < 0.01 in a multivariable regression model). CONCLUSIONS: Both the maternal and fetal mutated alleles of the PROGINS progesterone receptor polymorphism seem to protect from TTN. The same phenotype occurs regardless of whether the mutation is localized in the mother or in the infant. Fetal as well as maternal T2-alleles synergistically reduce the risk for TTN in a gene dose-dependent manner.
Asunto(s)
Receptores de Progesterona/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Adulto , Análisis de Varianza , Estudios de Cohortes , Femenino , Dosificación de Gen , Predisposición Genética a la Enfermedad , Alemania/epidemiología , Humanos , Recién Nacido , Masculino , Madres , Análisis Multivariante , Polimorfismo Genético , Embarazo , Análisis de Regresión , Síndrome de Dificultad Respiratoria del Recién Nacido/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Low birth weight is associated with an increased risk of cardiovascular events in later life. Insulin resistance is a key finding in adult patients with cardiovascular diseases. The neonatal phenotype of an individual with insulin resistance might be low birth weight, as insulin influences fetal growth. The renin-angiotensin-aldosterone system has been associated with cardiovascular disease and insulin resistance. We analyzed whether fetal polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme genes influence birth weight and/or fetal total glycated hemoglobin (fTGH), a surrogate parameter of fetal insulin resistance at birth. METHOD: In 1132 white women delivering singletons, neonatal umbilical blood samples and clinical data of the mothers and newborns were obtained. Newborns were genotyped with respect to the AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism. RESULTS: The AGT M235T TT polymorphism is associated with reduced birth weight (TT: 3288 g versus TM + MM: 3435 g, P < 0.05). Furthermore, newborns with a high percentage of fTGH (>6.5%) are more likely to have the TT genotype than those with normal fTGH (Asunto(s)
Angiotensinógeno/genética
, Peso al Nacer/genética
, Hemoglobina Glucada/metabolismo
, Insulina/genética
, Polimorfismo Genético
, Adulto
, Femenino
, Hemoglobina Fetal/genética
, Genotipo
, Humanos
, Recién Nacido
, Mutagénesis Insercional/genética
, Peptidil-Dipeptidasa A/genética
, Sistema Renina-Angiotensina/genética
, Eliminación de Secuencia/genética
RESUMEN
It was suggested that fetal sex may substantially affect maternal glycemic control during pregnancy in genetically susceptible mothers. The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is known to affect glycemic control and may act in a sex-specific manner. This polymorphism is thus an attractive candidate to test this hypothesis using a second independent functionally relevant polymorphism. We analyzed the impact of fetal sex on maternal glycemic control during pregnancy in relation to the maternal PPARgamma2 Pro12Ala polymorphism. Two-thousand fourteen Caucasian women without preexisting diabetes and preexisting hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department were genotyped. Glycemic control was analyzed by measuring total glycated hemoglobin at birth. Correction for confounding factors and multiple testing was considered in the analysis. The maternal PPARgamma2 Pro12Ala polymorphism without consideration of fetal sex had no effect on blood pressure, new onset of proteinuria and total glycated hemoglobin at delivery. Mothers carrying both G alleles (GG genotype) delivering a girl had a higher (P = 0.015) total glycated hemoglobin (6.81 or - 0.50%) versus mothers carrying the same alleles but delivering boys (5.85 + or - 0.58%). Comparing mothers with the GG genotype delivering girls with mothers with CC or CG genotypes also delivering girls (6.32 + or - 0.72%) revealed a significantly higher maternal total glycated hemoglobin at delivery in the former group (P < 0.009). Fetal sex/sex chromosomes may substantially affect maternal glycemic control in mothers who are carriers of the GG alleles of the PPARgamma2 Pro12Ala polymorphism.
Asunto(s)
Sustitución de Aminoácidos/genética , Glucemia/genética , Feto/fisiología , PPAR gamma/genética , Polimorfismo de Nucleótido Simple/genética , Caracteres Sexuales , Adulto , Alanina/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Embarazo , Prolina/genéticaRESUMEN
BACKGROUND: Recent evidence from very rare human diseases suggests that variation in the fetal genome can modify maternal physiology during pregnancy. Here, we tested the hypothesis that fetal sex as a major genetic variant of the fetal genome may affect maternal physiology during pregnancy in genetically susceptible pregnant women. METHODS: We analyzed the impact of fetal sex on maternal physiology during pregnancy in relationship with the maternal PROGINS progesterone receptor gene polymorphism. Two thousand and eighty-nine (2089) Caucasian women without preexisting diabetes and preexisting hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department participated in this study. RESULTS: The maternal PROGINS progesterone receptor polymorphism on its own had no effect on blood pressure, new onset of proteinuria, and total glycated hemoglobin at delivery. However, by considering the offspring's sex, the AA variant of the PROGINS progesterone receptor polymorphism was associated with profound cardiovascular/metabolic effects; mothers carrying both A alleles (AA genotype) delivering a boy had significantly lower systolic blood pressure during the first trimester of pregnancy versus AA mothers delivering girls (107.9+/-10.2 vs. 116.6+/-15.1 mmHg, P = 0.044). Diastolic blood pressure was similarly lower during the first trimester of pregnant AA women delivering boys in comparison with AA women delivering girls (63.4+/-5.7 vs. 68.2+/-10.9 mmHg, P = 0.032). Total glycated hemoglobin at delivery was significantly (P = 0.002) higher in AA mothers delivering boys (6.6+/-0.7%) versus AA mothers delivering girls (5.9+/-0.6%). CONCLUSION: Our study indicates that fetal sex may substantially affect maternal blood pressure as well as glycemic control during pregnancy in genetically susceptible mothers.