RESUMEN
The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21days (10mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action.
Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II/administración & dosificación , Diabetes Mellitus Tipo 2/genética , Hipertensión/genética , Receptor de Angiotensina Tipo 2/genética , Adiponectina/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Angiotensina II/metabolismo , Animales , Quimiocina CCL2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Imidazoles/administración & dosificación , Insulina/genética , Insulina/metabolismo , Resistencia a la Insulina/genética , Interleucina-6/genética , Losartán/administración & dosificación , Ratones , Ratones Noqueados , Piridinas/administración & dosificación , Receptor de Angiotensina Tipo 2/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Sleep apnea is characterized by increased sympathetic activity and is associated with systemic hypertension. Angiotensin (Ang) peptides have previously been shown to participate in the regulation of sympathetic tone and arterial pressure in the hypothalamic paraventricular nucleus (PVN) neurons. We investigated the role of endogenous Ang peptides within the PVN to control blood pressure in a rat model of sleep apnea-induced hypertension. Male Sprague-Dawley rats (250 g), instrumented with bilateral guide cannulae targeting the PVN, received chronic infusion of Ang antagonists (A-779, Ang-(1-7) antagonist; losartan and ZD7155, AT(1) antagonists; PD123319, AT(2) receptor antagonist, or saline vehicle). A separate group received an infusion of the GABA(A) receptor agonist (muscimol) to inhibit PVN neuronal activity independent of angiotensin receptors. After cannula placement, rats were exposed during their sleep period to eucapnic intermittent hypoxia (IH; nadir 5% O(2); 5% CO(2) to peak 21% O(2); 0% CO(2)) 20 cycles/h, 7 h/day, for 14 days while mean arterial pressure (MAP) was measured by telemetry. In rats receiving saline, IH exposure significantly increased MAP (+12±2 mm Hg vs. Sham -2±1 mm Hg P<0.01). Inhibition of PVN neurons with muscimol reversed the increase in MAP in IH rats (MUS: -9±4 mm Hg vs. vehicle +12±2 mm Hg; P<0.01). Infusion of any of the Ang antagonists also prevented the rise in MAP induced by IH (A-779: -5±1 mm Hg, losartan: -9±4 mm Hg, ZD7155: -11±4 mm Hg and PD123319: -4±3 mm Hg; P<0.01). Our results suggest that endogenous Ang peptides acting in the PVN contribute to IH-induced increases in MAP observed in this rat model of sleep apnea-induced hypertension.