RESUMEN
Previously, we demonstrated increased Angiotensin II type I receptor expression in leukocytes from patients with untreated, but not in treated, essential hypertension (essential hypertension). We hypothesized that the Angiotensin II AT1 receptor is also increased in leukocytes from patients with chronic kidney disease, however and can still be corrected with combined anti-hypertensive treatment with renin-angiotensin system (RAS) blockers and statins. Blood pressure, cholesterol, renal function oxidative stress parameters, inflammation, and leukocyte Angiotensin II AT1 receptor mRNA expression were measured both on and (6 weeks) off treatment. Data were compared to data of 10 healthy control subjects. Untreated chronic kidney disease patients (n=20) had higher blood pressure, cholesterol and leukocyte Angiotensin II AT1 receptor mRNA expression, but no different ox-LDL, thiobarbituric acid reactive substances, paraoxonase activity or hs-CRP. OxLDL and Lipoprotein(a) were increased in untreated chronic kidney disease. Angiotensin II AT1 receptor expression inversely correlated with renal function (R(2)=0.15, P<0.03) and Lipoprotein(a) but not with the other parameters. Treatment with RAS blockers and statins normalized blood pressure and cholesterol, however it did not correct enhanced leukocyte Angiotensin II AT1 receptor expression. Leukocyte Angiotensin II AT1 receptor expression is inappropriately high in chronic kidney disease, correlates inversely with renal function and does not depend on antihypertensive and lipid-lowering treatment. The uremic environment seems to dominate over previously reported actions of high blood pressure and cholesterol to enhance leukocyte Angiotensin II AT1 receptor expression.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Enfermedades Renales/sangre , Enfermedades Renales/genética , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Receptor de Angiotensina Tipo 1/genética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Enfermedad Crónica , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/fisiopatología , Masculino , Persona de Mediana Edad , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
Cardiovascular disease is still hard to predict in an individual. The main focus in cardiovascular research has been on endothelial cells and vascular smooth muscle cells of the vessel wall and their interactions with the blood flow. Alterations in the properties of the blood have received a lot of attention in biochemical terms. Interestingly, alterations in the properties of circulating cells have received less attention. We propose that presence of 1 or more risk factors together with normal physiological stimuli induce redox-dependent changes in leukocyte gene transcription with pathophysiological responses. Thus, risk factors render leukocytes hypersensitive to normal stimuli. Risk factors can be subdivided into physical and chemical factors. Superimposed on physiological regulators of leukocyte function, these risk factors promote a cellular pro-oxidative state. Redox-sensitive transcription factors are activated, leading to responses involving inflammation, adhesion, migration, and additional reactive oxygen species generation. As a consequence, monitoring of individual gene expression signatures of these cells could well increase our understanding of the mechanisms by which leukocytes and, in particular, monocytes function. Furthermore, transcriptomes of these cells could be used to investigate the aggressiveness of the atherosclerotic process or to guide treatment in the patient with risk factors for atherosclerosis.
Asunto(s)
Aterosclerosis/etiología , Aterosclerosis/fisiopatología , Células Sanguíneas , Aterosclerosis/diagnóstico , Aterosclerosis/terapia , Progresión de la Enfermedad , Humanos , Modelos CardiovascularesRESUMEN
Hypertension demands cardiac synthetic and metabolic adaptations to increased afterload. We studied gene expression in two models of mild hypertension without overt left ventricular hypertrophy using the NO synthase inhibitor nitro-L-arginine (L-NNA) and the glutathione depletor buthionine-S,R-sulfoximine (BSO). Mice were administered L-NNA, BSO, or water for 8 weeks. RNA of left ventricles was pooled per group, reverse transcribed, Cy3 and Cy5 labeled, and hybridized to cDNA microarrays. Normalized log(2) Cy3/Cy5 ratios of > or =0.7 or < or =-0.7 were considered significant. L-NNA and BSO both caused hypertension. Gene expression was regulated in cytoskeletal components in both models, protein synthesis in L-NNA-treated mice, and energy metabolism in BSO-treated mice. Energy metabolism genes shared several common transcription factor-binding sites such as Coup-Tf2, of which gene expression was increased in BSO-treated mice, and COMP-1. Characterization of the left ventricular adaptations as assessed with gene expression profiles reveals differential expression in energy and protein metabolism related to the pathogenetic background of the hypertension.
Asunto(s)
Metabolismo Energético/genética , Perfilación de la Expresión Génica , Corazón/efectos de los fármacos , Miocardio/metabolismo , Biosíntesis de Proteínas/genética , Animales , Sitios de Unión/genética , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Butionina Sulfoximina/farmacología , Análisis por Conglomerados , Inhibidores Enzimáticos/farmacología , Femenino , Expresión Génica/efectos de los fármacos , Glutamato-Cisteína Ligasa/antagonistas & inhibidores , Glutamato-Cisteína Ligasa/metabolismo , Glutatión/deficiencia , Glucólisis/genética , Corazón/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Hipertensión/inducido químicamente , Hipertensión/patología , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Ratones , Ratones Endogámicos C57BL , Miocardio/patología , Óxido Nítrico/deficiencia , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroarginina/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Tamaño de los Órganos/efectos de los fármacos , Proteinuria/orina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/metabolismoRESUMEN
We assessed whether large-scale expression profiling of leukocytes of patients with essential hypertension reflects characteristics of systemic disease and whether such changes are responsive to antihypertensive therapy. Total RNA from leukocytes were obtained from untreated (n=6) and treated (n=6) hypertensive patients without apparent end-organ damage and from normotensive controls (n=9). RNA was reverse-transcribed and labeled and gene expression analyzed using a 19-K oligonucleotide microarray using dye swaps. Samples of untreated and of treated patients were pooled for each sex and compared with age- and sex-matched controls. In untreated patients, 680 genes were differentially regulated (314 up and 366 down). In the treated patients, these changes were virtually absent (4 genes up, 3 genes down). A myriad of changes was observed in pathways involved in inflammation. Inflammation-dampening interleukin receptors were decreased in expression. Intriguingly, inhibitors of cytokine signaling (the PIAS family of proteins) were differentially expressed. The expression of several genes that are involved in regulation of blood pressure were also differentially expressed: angiotensin II type 1 receptor, ANP-A receptor, endothelin-2, and 3 of the serotonin receptors were increased, whereas endothelin-converting enzyme-1 was decreased. Strikingly, virtually no changes in gene expression could be detected in hypertensive patients who had become normotensive with treatment. This observation substantiates the long-standing idea that hypertension is associated with a complex systemic response involving inflammation-related genes. Furthermore, leukocytes display differential gene expression that is of importance in blood pressure control. Importantly, treatment of blood pressure to normal values can virtually correct such disturbances.
Asunto(s)
Antihipertensivos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Leucocitos/efectos de los fármacos , Adulto , Antihipertensivos/uso terapéutico , Femenino , Perfilación de la Expresión Génica , Humanos , Hipertensión/sangre , Inflamación/sangre , Inflamación/genética , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estrés MecánicoRESUMEN
BACKGROUND: Pseudovitamin D deficiency rickets (PDDR) is an autosomal disease, characterized by undetectable levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), rickets and secondary hyperparathyroidism. Mice in which the 25-hydroxyvitamin D3-1 alpha-hydroxylase (1 alpha-OHase) gene was inactivated, presented the same clinical phenotype as patients with PDDR. METHODS: cDNA Microarray technology was used on kidneys of 1 alpha-OHase knockout mice to study the expression profile of renal genes in this Ca2+-related disorder. Genome wide molecular events that occur during the rescue of these mice by high dietary Ca2+ intake were studied by the use of 15K cDNA microarray chips. RESULTS: 1 alpha-OHase knockout mice fed a normal Ca2+ diet developed severe hypocalcemia, rickets and died with an average life span of 12 +/- 2 weeks. Intriguingly, 1 alpha-OHase-/- mice supplemented with an enriched Ca2+ diet were normocalcemic and not significantly different from wild-type mice. Inactivation of the 1 alpha-OHase gene resulted in a significant regulation of +/- 1000 genes, whereas dietary Ca2+ supplementation of the 1 alpha-OHase-/- mice revealed +/- 2000 controlled genes. Interestingly, 557 transcripts were regulated in both situations implicating the involvement in the dietary Ca2+-mediated rescue mechanism of the 1 alpha-OHase-/- mice. Conspicuous regulated genes encoded for signaling molecules like the PDZ-domain containing protein channel interacting protein, FK binding protein type 4, kinases, and importantly Ca2+ transporting proteins including the Na+-Ca2+ exchanger, calbindin-D28K and the Ca2+ sensor calmodulin. CONCLUSION: Dietary Ca2+ intake normalized disturbances in the Ca2+ homeostasis due to vitamin D deficiency that were accompanied by the regulation of a subset of renal genes, including well-known renal Ca2+ transport protein genes, but also genes not previously identified as playing a role in renal Ca2+ handling.