ABSTRACT
La acción antiangiogénica de los inhibidores del receptor de angiotensina II (ARA II), ha sido documentada previamente, sin embargo, no ha sido descrita la relación entre angiogénesis e inhibidores directos de la renina (DRIs), los cuales participan regulando el sistema renina-angiotensina-aldosterona (SRAA). El objetivo fue demostrar el efecto antiangiogénico de aliskireno, un DRI, en membranas alantocoriónicas (MAC) de pollo, para lo cual fueron instilados aliskireno y enalapril sobre MAC en distintas concentraciones para realizar su comparación posterior. En secciones histológicas seriadas se registró el número de vasos sanguíneos presentes en 9000 µm2 bajo microscopio de luz a máximo aumento, y se realizó análisis estadístico utilizando ANOVA y el test de Tukey para demostrar posibles diferencias. Los receptores tratados con aliskireno, en ambas concentraciones utilizadas, presentaron menor densidad vascular, en comparación con los controles, siendo ésta estadísticamente significativa a mayor concentración. Aliskireno en concentraciones altas tiene un efecto antiangiogénico en un modelo experimental de MAC. Este hallazgo plantea la necesidad de estudios posteriores, dada la proyección que podría tener el uso inhibidores directos de la renina. A partir de estos resultados, se podría pensar en la factibilidad del uso de aliskireno para la modulación de la angiogénesis en diversas enfermedades crónicas no transmisibles.
Angiogenesis is the formation of new blood vessels from pre-existing ones. Antiangiogenic effect of angiotensin receptor blockers has been reported, however, the relationship between direct renin inhibitors and angiogenesis has not been well described. To assess the antiangiogenic effect of aliskiren, a direct renin inhibitor, on chick embryo chorioallantoic membrane (CAM) assay. Aliskiren and enalapril were instilled in different concentrations and compared. In serial histological sections, the number of blood vessels per 9000 µm2 area under observation through optical microscope using maximum zoom, was registered. Statistical analysis using Anova and Tukey test in order to show possible differences, was performed. Receptors treated with aliskiren presented lower vascular density, which was statistically significant when a higher concentration was administered. High concentrations of aliskiren have an antiangiogenic effect on CAM assay. This finding means further studies are needed, because of the usefulness direct renin inhibitors could have. These results, also, might enhance the possibility of using aliskiren for regulating angiogenesis in the context of non-transmissible chronic diseases.
Subject(s)
Animals , Amides/pharmacology , Chorioallantoic Membrane/drug effects , Fumarates/pharmacology , Neovascularization, Physiologic/drug effects , Analysis of Variance , Chick Embryo , Enalapril/pharmacology , Models, Animal , Renin/antagonists & inhibitorsABSTRACT
BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.
Subject(s)
Animals , Male , Amides/pharmacology , Angiotensin II/pharmacology , Disease Models, Animal , Fibrosis , Fumarates/pharmacology , Kidney/drug effects , Mice, Inbred C57BL , Mice, Knockout , Nephritis, Interstitial/genetics , RNA, Messenger/genetics , Renin/antagonists & inhibitors , Renin-Angiotensin System/drug effects , Toll-Like Receptor 2/deficiency , Ureteral Obstruction/drug therapyABSTRACT
Hypertension is one of the major causes of cardiovascular morbidity. Most patients who are on treatment for hypertension fail to achieve adequate control with the existing therapy and rates of cardiovascular morbidity remain high. As the renin-angiotensin-aldosterone system is strongly implicated in the development of hypertension-related target organ damage, intensive efforts have been devoted towards the development of drugs targeting this system. In addition to angiotensin converting enzyme inhibitors and angiotensin receptor blockers, inhibition of renin has also become a clinical reality. Aliskiren, a novel renin inhibitor, has overcome a number of shortcomings of existing drugs and is now available to address angiotensin production directly at its rate-limiting step.
Subject(s)
Amides/chemistry , Fumarates/chemistry , Humans , Hypertension/drug therapy , Renin/antagonists & inhibitorsSubject(s)
Administration, Oral , Amides/administration & dosage , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Fumarates/administration & dosage , Humans , Hypertension/diagnosis , Randomized Controlled Trials as Topic , Renin/antagonists & inhibitors , Treatment OutcomeABSTRACT
O sistema renina-angiotensina desempenha papel preponderante na homeostase cardiovascular, principalmente mantendo controle dinâmico da volemia e da resistência vascular periférica. Contudo, desajustes do sistema parecem estar envolvidos no surgimento e/ou na manutenção da hipertensão arterial, da insuficiência caardíaca e da esclerose glomerular. A intervenção farmacológica sobre as várias etapas do sistema renina-angiotensina tem repetidamente comprovado controlar a pressão arterial a níveis normais, além de reduzir significativamente a hipertrofia ventricular esquerda; nos pacientes com insuficiência cardíaca ou pós-infarto do miocárdio, os inibidores da enzima conversora da angiotensina (ECA) promovem remodelação miocárdica com melhora da função cardíaca, além de promover aumento na sobrevida desses pacientes. Em pacientes diabéticos com proteinúria e graus variáveis de perda da função renal, os inibidores da ECA também têm determinado alterações importantes na história natural dessa doença, reduzindo a proteinúria e a velocidade de perda da massa funcionante renal.