Association between Diastolic Dysfunction with Inflammation and Oxidative Stress in Females ob/ob Mice

Objective: To evaluate autonomic and cardiovascular function, as well as inflammatory and oxidative stress markers in ob/ob female mice. Methods: Metabolic parameters, cardiac function, arterial pressure (AP), autonomic, hormonal, inflammatory, and oxidative stressmarkers were evaluated in 12-weeks female wild-type (WT group) and ob/ob mice (OB group). Results: OB animals showed increased body weight, blood glucose, and triglyceride levels, along with glucose intolerance, when compared to WT animals. Ejection fraction (EF) and AP were similar between groupshowever, the OB group presented diastolic dysfunction, as well as an impairment on myocardial performance index. Moreover, the OB group exhibited important autonomic dysfunction and baroreflex sensitivity impairment, when compared to WT group. OB group showed increased Angiotensin II levels in heart and renal tissuesdecreased adiponectin and increased inflammatory markers in adipose tissue and spleen. Additionally, OB mice presented a higher damage to proteins and lipoperoxidation and lower activity of antioxidant enzymes in kidney and heart. Correlations were found between autonomic dysfunction with angiotensin II and inflammatory mediators, as well as between inflammation and oxidative stress. Conclusions: Our results showed that female adult ob/ob mice presented discrete diastolic dysfunction accompanied by autonomic disorder, which is associated with inflammation and oxidative stress in these animals.CAPESCNPqFAPESPCNPq Fellowship (CNPq-BPQ)Univ São Paulo, Fac Med, Heart Inst InCor, Hypertens Unit, São Paulo, BrazilUniv Nove Julho, Translat Physiol Lab, São Paulo, BrazilNova Southeastern Univ, Inst Neuro Immune Med, Dept Integrat Immunol Cardiovasc Res, Ft Lauderdale, FL 33314 USAUniv Fed São Paulo, Dept Med, Nephrol Div, São Paulo, BrazilUniv Estadual Campinas, Fac Phys Educ, Dept Adapted Phys Act, Campinas, SP, BrazilUniv Fed São Paulo, Dept Med, Nephrol Div, São Paulo, BrazilCNPq: 457200/2014-6CNPq: 401781/2012-7CNPq: 479076/2012-0CNPq: 563961/2010-4FAPESP: 2015/11223-6FAPESP: 2011/15828-9FAPESP: 2010/17188-4Web of Scienc

Tonin Overexpression in Mice Diminishes Sympathetic Autonomic Modulation and Alters Angiotensin Type 1 Receptor Response

Background: Tonin, a serine-protease that forms Angiotensin II (AngII) from angiotensinogen, is increased in failing human heart samples. Increased blood pressure (BP) and decreased heart rate (HR) variabilities are associated with higher risk of cardiovascular morbidity. Losartan has been used to reduce hypertension and, therefore, lowers the risk of fatal and non-fatal cardiovascular events. Determination of tonin's impact on BP and HR variabilities as well as the impact of losartan remain questions to be elucidated.Aim: Evaluation of cardiovascular autonomic profile in transgenic mice overexpressing the rat tonin enzyme TGM'(rton) and the impact of AT1 receptor blocker, losartan.Methods: Male C57BL/6 (WT) and TGM'(rTon) mice were cannulated for recording BP (Windaq, 4 MHz) for 30 min at baseline and 30 min after losartan injection (20 mg/kg). BP and HR variabilities were analyzed in time and frequency domain method. Low-frequency (LF) and high-frequency (HF) components were identified for sympathetic and parasympathetic modulations analysis. Ang I, AngII, and Ang1-7 were quantified by high performance liquid chromatography method. The total enzymatic activity for AngI, AngII, and Ang1-7 formation was evaluated in the heart and plasma by Liquid chromatography mass spectrometry (LC-MS/MS).Results: At the baseline TGM'(rTon) exhibited higher BP, lower cardiac LF, higher cardiac HF, lower LF/HF, and lower alpha index than wild type (WT). After losartan injection, TGM'(rTon) mice presented an additional decrease in cardiac LF and increase in HF in relation to baseline and WT. In the vasculature, losartan caused decreased in BP and LF of systolic BP in WT mice in relation to its baseline. A similar effect was observed in the BP of TGM'(rTon) mice; however, LF of systolic BP increased compared to baseline. Our data also indicates that AT1R receptor signaling has been altered in TGM’(rTon)mice. Interestingly, the dynamics of the renin-angiotensin system kinetics change, favoring production of Ang1-7.Conclusion: Autonomic evaluation of TGM’(rTon) mice indicates an unclear prognosis for diseases that affect the heart. HR variability in TGM’(rTon) mice indicates high risk of morbidity, and sympathetic and parasympathetic modulation indicate low risk of morbidity. The low risk of morbidity could be the biased production of Ang1-7 in the heart and circulation; however, the altered response of AT1R in the TGM’(rTon) remains to be elucidated, as well aswhether that signaling is pro-protection or pro-pathology

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

Background: the clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods: 2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).Results: the 2K1C mice exhibited normal plasma levels of Ang I, II and 1-7, whereas the intrarenal Ang I and II were increased (similar to 35% and similar to 140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (similar to 45%) and intrarenal (+15%) Ang 1-7. the 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.Conclusion: These data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)State Agency for the Development of Science and Technology (FAPES/Universal)Univ Fed Espirito Santo, Hlth Sci Ctr, Lab Translat Physiol, Vitoria, ES, BrazilEmescam Sch Hlth Sci, Vitoria, ES, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniv Fed Espirito Santo, Hlth Sci Ctr, Pharmaceut Sci Grad Program, Vitoria, ES, BrazilUniv Fed Paraiba, Hlth Sci Ctr, Dept Physiol & Pathol, BR-58059900 Joao Pessoa, PB, BrazilUVV, Pharmaceut Sci Grad Program, Vila Velha, ES, BrazilFed Inst Educ Sci & Technol IFES, Vila Velha, ES, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilCNPq: 302582/2011-8CNPq: 476525/2012-8CNPq: 305188/2012-7CNPq: 473177/2013-7State Agency for the Development of Science and Technology (FAPES/Universal): 012/2011State Agency for the Development of Science and Technology (FAPES/Universal): 54498465CNPq: 012/2009Web of Scienc

Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

Background: Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra (R)) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity.Methods: the experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/ day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained.Results: Sildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). in addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice.Conclusions: Our data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)State Agency for the Development of Science and Technology (FAPES)Univ Fed Espirito Santo, Hlth Sci Ctr, Lab Translat Physiol, Vitoria, ES, BrazilUniv Fed Paraiba, Hlth Sci Ctr, Dept Physiol & Pathol, BR-58059900 Joao Pessoa, Paraiba, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniv Vila Velha, Pharmaceut Sci Grad Program, Vila Velha, ES, BrazilFed Inst Educ Sci & Technol IFES, Vila Velha, ES, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilCNPq: 302582/2011-8CNPq: 476525/2012-8CNPq: 305188/2012-7CNPq: 473177/2013-7State Agency for the Development of Science and Technology (FAPES): 54498465CNPq: 012/2009Web of Scienc

Intra-Renal Angiotensin Levels Are Increased in High-Fructose Fed Rats in the Extracorporeal Renal Perfusion Model

Overconsumption of fructose leads to metabolic syndrome as a result of hypertension, insulin resistance, and hyperlipidemia. In this study, the renal function of animals submitted to high fructose intake was analyzed from weaning to adulthood using in vivo and ex vivo methods, being compared with a normal control group. We investigated in ex vivo model of the role of the renin Angiotensin system (RAS) in the kidney. The use of perfused kidney from animals submitted to 8-week fructose treatment showed that high fructose intake caused metabolic and cardiovascular alterations that were consistent with other studies. Moreover, the isolated perfused kidneys obtained from rats under high fructose diet showed a 33% increase in renal perfusion pressure throughout the experimental period due to increased renal vascular resistance and a progressive fall in the glomerular filtration rate, which reached a maximum of 64% decrease. Analysis of RAS peptides in the high fructose group showed a threefold increase in the renal concentrations of angiotensin I (Ang I) and a twofold increase in angiotensin II (Ang II) levels, whereas no change in angiotensin 1-7 (Ang 1-7) was observed when compared with the control animals. We did not detect changes in angiotensin converting enzyme (ACE) activity in renal tissues, but there is a tendency to decrease. These observations suggest that there are alternative ways of producing Ang II in this model. Chymase the enzyme responsible for Ang II formation direct from Ang I was increased in renal tissues in the fructose group, confirming the alternative pathway for the formation of this peptide. Neprilysin (NEP) the Ang 1-7 forming showed a significant decrease in activity in the fructose vs. control group, and a tendency of reduction in ACE2 activity. Thus, these results suggest that the Ang 1-7 vasodilator peptide formation is impaired in this model contributing with the increase of blood pressure. In summary, rats fed high fructose affect renal RAS, which may contribute to several deleterious effects of fructose on the kidneys and consequently an increase in blood pressure

Desarrollo de habilidades de interacción social en niños con conductas disruptivas en la institución educativa: cuna-jardín n° 52 “Señor De Luren” - Ica -2017

Los términos habilidades de interacción social y conductas disruptivas en niños, tiene significados diferentes, se interpreta según los conocimientos y la experiencia que tenga una persona. La investigación que presentamos para obtener el Título Profesional de Licenciada en Educación Inicial “DESARROLLO DE HABILIDADES DE INTERACCIÓN SOCIAL EN NIÑOS CON CONDUCTAS DISRUPTIVAS EN LA INSTITUCIÓN EDUCATIVA: CUNA – JARDIN N° 52 “SEÑOR DE LUREN” - ICA -2017. Tiene como propósito de estudio: Determinar cómo las relaciones familiares propician el desarrollo de habilidades de interacción social para la resolución de conductas disruptivas en niños de la Institución Educativa: Cuna- Jardín N° 52 “Señor de Luren” – 2017. Que nos permitió contrastar la hipótesis de estudio: Las óptimas relaciones familiares estimulan oportunamente el desarrollo de habilidades de interacción social disminuyendo significativamente las conductas disruptivas en niños de la Institución Educativa: Cuna – Jardín N° 52 "Señor de Luren” - Ica 2017. La conclusión principal fue: Las óptimas relaciones familiares estimulan oportunamente el desarrollo de habilidades de interacción social disminuyendo significativamente las conductas disruptivas en niños en el jardín, evitándose que se lastimen los niños durante las actividades educativas, para lograr óptimos aprendizajesTesi