Aims. In this work, we analyse the multiwavelength brightness variations and flaring activity of FSRQ PKS 1510-089, aiming to constrain the position of the emission sources. Methods. We report 7 mm ...(43 GHz) radio and R-band polarimetric observations of PKS 1510-089. The radio observations were performed at the Itapetinga Radio Observatory, while the polarimetric data were obtained at the Pico dos Dias Observatory. The 7 mm observations cover the period between 2011 and 2013, while the optical polarimetric observations were made between 2009 and 2012. Results. At 7 mm, we detected a correlation between four radio and γ-ray flares with a delay of about 54 days between them; the higher frequency counterpart occurred first. Using optical polarimetry, we detected a large variation in polarization angle (PA) within two days associated with the beginning of a γ-ray flare. Complementing our data with other data obtained in the literature, we show that PA presented rotations associated with the occurrence of flares. Conclusions. Our results can be explained by a shock-in-jet model, in which a new component is formed in the compact core producing an optical and/or γ-ray flare, propagates along the jet, and after some time becomes optically thin and is detected as a flare at radio frequencies. The variability in the polarimetric parameters can also be reproduced; we can explain large variation in both PA and polarization degree (PD), in only one of them, or in neither, depending on the differences in PA and PD between the jet and the new component.
Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. ...Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown.
Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension.
Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice.
The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
The angiotensin II type 2 (AT
) receptor has a role in promoting insulin sensitivity. However, the mechanisms underlying the AT
receptor-induced facilitation of insulin are still not completely ...understood. Therefore, we investigated whether acute in vivo administration of AT
receptor agonist compound 21 (C21) could activate insulin signaling molecules in insulin-target tissues. We report that, in male C57BL/6 mice, an acute (5 min, 0.25 mg/kg; i.v.) injection of C21 induces the phosphorylation of Akt and ERK1/2 at activating residues (Ser473 and Thr202/Tyr204, respectively) in both epididymal white adipose tissue (WAT) and heart tissue. In WAT, the extent of phosphorylation (p) of Akt and ERK1/2 induced by C21 was approximately 65% of the level detected after a bolus injection of a dose of insulin known to induce maximal activation of the insulin receptor (IR). In the heart, C21 stimulated p-Akt to a lesser extent than in WAT and stimulated p-ERK1/2 to similar levels to those attained by insulin administration. C21 did not modify p-IR levels in either tissue. We conclude that in vivo injection of the AT
receptor agonist C21 activates Akt and ERK1/2 through a mechanism that does not involve the IR, indicating the participation of these enzymes in AT
R-mediated signaling.
The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of ...insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and female AT2R knockout (KO) mice. When compared to the respective wild-type (WT) group, glycemia and insulinemia was unaltered in AT2RKO mice regardless of sex. However, female AT2RKO mice displayed decreased insulin sensitivity compared to their WT littermates. This was accompanied by a compensatory increase in adiponectinemia and with a specific attenuation of the activity of main insulin signaling components (insulin receptor, Akt and ERK1/2) in adipose tissue with no apparent alterations in insulin signaling in either liver or skeletal muscle. These parameters remained unaltered in male AT2RKO mice as compared to male WT mice. Present data show that the AT2R has a physiological role in the conservation of insulin action in female but not in male mice. Our results suggest a sexual dimorphism in the control of insulin action and glucose homeostasis by the AT2R and reinforce the notion that pharmacological modulation of the balance between the AT1R and AT2R receptor could be important for treatment of metabolic syndrome and type 2 diabetes.
•AT2RKO mice present a sexual dimorphism in terms of insulin sensitivity.•AT2R deletion impairs insulin tolerance in female mice.•AT2RKO does not affect insulin sensitivity in male mice.•In female mice, AT2R deficiency leads to a selective attenuation of insulin signaling in adipose tissue.•AT2R in adipose tissue appears to have a major role in the control of insulin action.
The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many ...cases, this pathological condition is linked to a cluster of metabolic disorders, such as obesity, systemic hypertension and dyslipidaemia, defined as the metabolic syndrome. Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between AngII (angiotensin II) and the insulin signalling pathway has been the focus of great interest in the last decade. Indeed, substantial evidence has shown that anti-hypertensive drugs that block the RAS (renin-angiotensin system) may also act to prevent diabetes. Despite its long history, new components within the RAS continue to be discovered. Among them, Ang-(1-7) angiotensin-(1-7) has gained special attention as a counter-regulatory hormone opposing many of the AngII-related deleterious effects. Specifically, we and others have demonstrated that Ang-(1-7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that insulin and Ang-(1-7) share a common intracellular signalling pathway. We also address the molecular mechanisms behind the beneficial effects of Ang-(1-7) on AngII-mediated insulin resistance. Finally, we discuss potential therapeutic approaches leading to modulation of the ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7)/Mas receptor axis as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.
Dietary fructose causes salt-sensitive hypertension. Proximal tubules (PTs) reabsorb 70% of the filtered NaCl. Angiotensin II (Ang II), atrial natriuretic peptide (ANP) and norepinephrine (NE) ...regulate this process. Although Ang II signaling blockade ameliorates fructose-induced salt-sensitive hypertension, basal PT Na⁺ reabsorption and its sensitivity to the aforementioned factors have not been studied in this model. We hypothesized consuming fructose with a high-salt diet selectively enhances the sensitivity of PT transport to Ang II. We investigated the effects of Ang II, ANP and NE on PT Na reabsorption in rats fed a high-salt diet drinking tap water (HS) or 20% fructose (HS-FRU). Oxygen consumption (QO₂) was used as a measure of all ATP-dependent transport processes. Na⁺/K⁺-ATPase and Na⁺/H⁺-exchange (NHE) activities were studied because they represent primary apical and basolateral transporters in this segment. The effect of 10
mol/L Ang II in QO₂ by PTs from HS-FRU was larger than HS (
< 0.02;
= 7). In PTs from HS-FRU 10
mol/L Ang II stimulated NHE activity by 2.6 ± 0.7 arbitrary fluorescence units/s (
< 0.01;
= 5) but not in those from HS. The stimulatory effect of Ang II on PT Na⁺/K⁺-ATPase activity was not affected by HS-FRU. Responses of QO₂ and NHE activity to ANP did not differ between groups. The response of QO₂ to NE was unaltered by HS-FRU. We concluded that the sensitivity of PT Na⁺ reabsorption specifically to Ang II is enhanced by HS-FRU. This maintains high rates of transport even in the presence of low concentrations of the peptide, and likely contributes to the hypertension.
Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the ...present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls lean Zucker rats (LZR) were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng·kg(-1)·min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy.
Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR) is the only intervention that reliably increases mouse ...longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO) in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15%) CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30%) CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT) in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT) in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.
In the present study we have used hypopituitary Ames dwarf mice, which lack GH, prolactin and TSH, to investigate the consequences of the deficiency of these hormones on glucose homeostasis and on ...the initial components of the insulin signal transduction pathway in the liver. Ames dwarf mice displayed hypersensitivity to insulin since they maintained lower fasting glucose concentrations (73% of control values), had significantly reduced amounts of insulin (58% of control values), and exhibited an increased hypoglycemic response to exogenous insulin. Probably as a result of reduced insulin production, Ames dwarf mice displayed intolerance to glucose. The insulin-stimulated phosphorylation of the insulin receptor (IR) tended to be increased in the liver of Ames dwarf mice, while IR receptor protein content was increased by 38%. Insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 was increased by 61 and 72% respectively, while IRS-1 and IRS-2 protein levels were increased by 76 and 95%. The insulin-stimulated association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 was increased by 28%, but unaltered with IRS-2. Interestingly, while the insulin-stimulated phosphotyrosine-derived PI 3-kinase activity was not changed, insulin-stimulated protein kinase B activation was increased by 41% in this tissue. These alterations may account for the insulin hypersensitivity exhibited by these animals. The present findings in long-lived Ames dwarf mice add to the evidence that insulin signaling is importantly related to the regulation of aging and life span.
Fructose-enriched diets cause salt-sensitive hypertension. Proximal tubules (PTs) reabsorb 70% of the water and salt filtered through the glomerulus. Angiotensin II (Ang II) regulates this process. ...Normally, dietary salt reduces Ang II allowing the kidney to excrete more salt, thereby preventing hypertension. We hypothesized that fructose-enriched diets enhance the ability of low concentrations of Ang II to stimulate PT transport. We measured the effects of a low concentration of Ang II (10
mol/L) on transport-related oxygen consumption (QO₂), and Na/K-ATPase and Na/H-exchange (NHE) activities and expression in PTs from rats consuming tap water (Control) or 20% fructose (FRUC). In FRUC-treated PTs, Ang II increased QO₂ by 14.9 ± 1.3 nmol/mg/min (
< 0.01) but had no effect in Controls. FRUC elevated NHE3 expression by 19 ± 3% (
< 0.004) but not Na/K-ATPase expression. Ang II stimulated NHE activity in FRUC PT (Δ + 0.7 ± 0.1 Arbitrary Fluorescent units (AFU)/s,
< 0.01) but not in Controls. Na/K-ATPase activity was not affected. The PKC inhibitor Gö6976 blocked the ability of FRUC to augment the actions of Ang II. FRUC did not alter the inhibitory effect of dopamine on NHE activity. We conclude that dietary fructose increases the ability of low concentrations of Ang II to stimulate PT Na reabsorption via effects on NHE.
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