Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in ...response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1-7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1β, associated with cardiomyocytes' diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes' diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1-7) content. Our data indicate that early training-induced downregulation of LV ACE-AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro-inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation.
Sepsis is an uncontrolled systemic inflammatory response against an infection and a major public health issue worldwide. This condition affects several organs, and, when caused by Gram-negative ...bacteria, kidneys are particularly damaged. Due to the importance of renin-angiotensin system (RAS) in regulating renal function, in the present study, we aimed to investigate the effects of endotoxemia over the renal RAS. Wistar rats were injected with Escherichia coli lipopolysaccharide (LPS) (4 mg/kg), mimicking the endotoxemia induced by Gram-negative bacteria. Three days after treatment, body mass, blood pressure, and plasma nitric oxide (NO) were reduced, indicating that endotoxemia triggered cardiovascular and metabolic consequences and that hypotension was maintained by NO-independent mechanisms. Regarding the effects in renal tissue, inducible NO synthase (iNOS) was diminished, but no changes in the renal level of NO were detected. RAS was also highly affected by endotoxemia, since renin, angiotensin-converting enzyme (ACE), and ACE2 activities were altered in renal tissue. Although these enzymes were modulated, only angiotensin (ANG) II was augmented in kidneys; ANG I and ANG 1-7 levels were not influenced by LPS. Cathepsin G and chymase activities were increased in the endotoxemia group, suggesting alternative pathways for ANG II formation. Taken together, our data suggest the activation of noncanonical pathways for ANG II production and the presence of renal vasoconstriction and tissue damage in our animal model. In summary, the systemic administration of LPS affects renal RAS, what may contribute for several deleterious effects of endotoxemia over kidneys.
The present study investigated the angiotensin II (Ang II) responses in rat femoral veins taken from 2-kidney-1clip (2K1C) hypertensive rats at 4 weeks after clipping, as well as the effects of ...exercise on these responses. In this manner, femoral veins taken from 2K1C rats kept at rest or exposed to acute exercise or to exercise training were challenged with Ang II or endothelin-1 (ET-1) in organ bath. Simultaneously, the presence of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were determined in these preparations by western blotting. In these experiments, femoral veins exhibited subdued Ang II responses. However, after nitric oxide (NO) synthesis blockade, the responses were higher in the femoral veins taken from animals kept at rest 0.137(0.049-0.245);
= 10 than those obtained in trained animals kept at rest 0.008(0.001-0.041);
= 10 or studied after a single bout of exercise 0.001(0.001-0.054);
= 11. In preparations in which, in addition to NO synthesis, both the local production of prostanoids and the action of ET-1 on type A (ET
) or B (ET
) receptors were inhibited, the differences induced by exercise were no longer observed. In addition, neither ET-1 responses nor the presence of COX-1 and COX-2 in these preparations were modified by the employed exercise protocols. In conclusion, NO maintains Ang II responses reduced in femoral veins of 2K1C animals at rest. However, vasodilator prostanoids as well as other relaxing mechanisms, activated by ET
stimulation, are mobilized by exercise to cooperate with NO in order to maintain controlled Ang II responses in femoral veins.
According to the International Diabetes Federation, the number of people with diabetes mellitus may reach 700 million in 2045. Catecholamines are involved in the regulation of several kidney ...functions. This study investigates the effects of hyperglycemia on catecholamines' metabolism in kidney tissue from control, diabetic, and insulin-treated diabetic rats, both in vivo and in vitro.
Male Wistar-Hannover rats were randomized into: control, diabetic, and insulin-treated diabetic groups. Diabetes was induced by a single injection of streptozotocin, and diabetic treated group also received insulin. After 60 days, blood and kidney tissue from all groups were collected for catecholamines' quantification and mesangial cells culture.
diabetic rats had lower body weight, hyperglycemia, and increase water intake and diuresis. Additionally, diabetes promoted a sharp decrease in creatinine clearance compared to control group. Regarding the whole kidney extracts, both diabetic groups (treated and non-treated) had significant reduction in norepinephrine concentration. In mesangial cell culture, catecholamines' concentration were lower in the culture medium than in the intracellular compartment for all groups. Norepinephrine, epinephrine, and dopamine medium levels were increased in the diabetic group.
The major finding of the present study was that 8 weeks of diabetes induction altered the kidney catecholaminergic system in a very specific manner, once the production of catecholamines in the excised kidney tissue from diabetic rats was differentially modulated as compared with the production and secretion by cultured mesangial cells.
Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). ...The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1–7). Increased concentration of renal Ang-(1–7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication.
•Chronic mild unpredictable stress increased depressive-like behavior.•Chronic mild unpredictable stress induces cognitive impairment.•Chronic mild unpredictable stress increased hypothalamic ...angiotensin II.•Handling and losartan cancelled behavior responses induced by stress.•Handling and losartan decreased and cancelled respectively stress-induced hypothalamic angiotensin II secretion.
Physical touch can help to decrease the effects of stress. The aim of this study was to evaluate the influence of tactile stimulation on the hormonal and behavioral responses of young adult rats submitted to chronic mild unpredictable stress (CMS), considering the role of angiotensin II (Ang II). In Experiment 1, male rats were divided into 4 groups: control, stress, tactile stimulation (TS), and stress + TS. CMS was applied for three weeks. Tactile stimulation was applied for seven weeks, five days a week. After the CMS protocol, depression-like behaviors were evaluated by forced swimming and sucrose consumption tests. Learning and memory were evaluated using the Y-maze test. Fifteen days after the CMS procedure, the animals were euthanized and the levels of stress hormones were determined. The hypothalamus was isolated for determination of the Ang II concentration. In Experiment 2, control and stressed rats, with or without treatment using losartan (angiotensin II type 1 receptor blocker), were evaluated using the same behavioral tests and the hypothalamus Ang II concentration was also determined. CMS increased plasma corticosterone, norepinephrine, and epinephrine concentrations, induced depression-like behaviors, impaired learning and memory, and increased the Ang II concentration in the hypothalamus. Tactile stimulation attenuated these stress-induced effects. Losartan treatment effectively prevented increase of the hypothalamic Ang II concentration and the development of depression-like behavior, and also reduced the impairment of learning and memory in the stressed animals. The results indicated that tactile stimulation seemed to protect adult rats against hormonal and behavioral chronic stress effects, and that Ang II could be involved in the CMS effects.
•Chronic mild unpredictable stress induced depressive-like behavior.•Chronic mild unpredictable stress caused learning and memory impairment.•Chronic mild unpredictable stress induced hyperactivity ...of the RAS.•Environmental enrichment protected against behavioral changes induced by stress.•Environmental enrichment mitigated stress-induced hypothalamic Ang II increase.
Environmental enrichment (EE) has been studied as a protocol that can improve brain plasticity and may protect against negative insults such as chronic stress. The aim of this study was to evaluate the effects of EE on the hormonal and behavioral responses induced by chronic mild unpredictable stress (CMS) in rats, considering the involvement of the renin-angiotensin system. Male adult rats were divided into 4 groups: control, CMS, EE, and CMS + EE, and the experimental protocol lasted for 7 weeks. EE was performed during 7 weeks, 5 days per week, 2 h per day. CMS was applied during weeks 3, 4, and 5. After the CMS (week 6), depression-like behavior was evaluated by forced swimming and sucrose consumption tests, anxiety level was evaluated using the elevated plus-maze test, and memory was evaluated using the Y-maze test. On week 7, the animals were euthanized and basal plasma levels of corticosterone and catecholamines were determined. The hypothalamus was isolated and tissue levels of angiotensin peptides were evaluated. CMS increased plasma corticosterone, norepinephrine, and epinephrine basal concentrations, induced depression-like behaviors, impaired memory, and increased hypothalamic angiotensin I, II, and IV concentrations. EE decreased stress hormones secretion, depression-like behaviors, memory impairment, and hypothalamic angiotensin II induced by stress. Reductions of anxiety-like behavior and norepinephrine secretion were observed in both stressed and unstressed groups. The results indicated that EE seemed to protect adult rats against hormonal and behavioral CMS effects, and that the reduction of angiotensin II could contribute to these effects.
Diabetes Mellitus (DM) cause a great amount of complications in several organs, developing chronic diseases as diabetic retinopathy, diabetic nephropathy and cardiovascular diseases. This study ...analyzed the catecholamines (CAs) profile in renal tissue and primary mesangial cells (MC), from normal and diabetic animals. DM was induced in Wistar–Hannover by streptozotocin single tail injection (50mg/kg). The groups ‐ Control (CT), Hyperglycemic (HG) and Insuline Treated Diabetic (TD), were evaluated during 60 days. CAs concentrations were determined by HPLC‐ED. The analysis of CAs in primary MC demonstrated statistically significant increased in the CA levels in HG compared to TD and CT. The CAs renal levels, showed that Norepinephrine is significantly diminished in HG. On the other hand, the other CAs did not present significant difference between the groups. Overall, we can suggest that MC behave in a different manner from global renal tissue and this difference suggests an important role in the production of these hormones that could have a local activity regulating the glomerular filtration. Concluding that in DM we may find a disturb CAs metabolism, besides the renal damage induced directly by high blood glucose levels and these alterations could contribute to the diabetic nephropathy development. Supported by FAPESP, 09/50738‐0.
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The aim of this study is to analyze the catecholamines (CA) profile in mesangial cells (MC) from normal and diabetic animals. The diabetes mellitus has been induced in Wistar‐Hannover ...by injection of streptozotocin (50mg/kg). Three groups of study ‐ Control (CT), Hyperglycemic (HG) and treated Diabetic (TD), were evaluated during 60 days. MCs were obtained through sieve fractionation and collagenase‐treatment, and collected in the third subculture. CA concentrations were determined by high performance liquid chromatography. CA concentrations in the MC extracellular medium (EM) and intracellular compartment (IC) of the CT group expressed in pg/mg of cellular protein were respectively: Norepinephrine (NE), 18.1±1.1; Epinephrine (EP), 10.0±0.6; Dopamine (DE), and NE, 117.3±10.1; AD, 62.6±9.4; DE, 39.1±7.7. The levels of CA detected for HG in the EM were NE, 43.5±5.8; EP, 149.0±33.6; DE, 57.9±11.2 and in the IC were NE, 109.4±41.3; EP, 269.6±22,3; DE, 189.1±48.9. The comparison between groups demonstrated statistically significant differences in the CA levels of TD‐HG and for CT‐HG (TD and CT had a similar behavior). Thus, we can suggest that besides the renal damage induced directly by high blood glucose levels, DM could disturb CA metabolism and contribute to the development of diabetic nephropathy. Supported by FAPESP 02/13290‐2.
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