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An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant Staphylococcus aureus (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans.
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We examined the effects of an acute increase in blood pressure (BP) and renal sympathetic nerve activity (rSNA) induced by bicuculline (Bic) injection in the paraventricular nucleus of hypothalamus (PVN) or the effects of a selective increase in rSNA induced by renal nerve stimulation (RNS) on the renal excretion of sodium and water and its effect on sodium-hydrogen exchanger 3 (NHE3) activity. Uninephrectomized anesthetized male Wistar rats were divided into three groups: (1) Sham; (2) Bic PVN: (3) RNS + Bic injection into the PVN. BP and rSNA were recorded, and urine was collected prior and after the interventions in all groups. RNS decreased sodium (58%) and water excretion (53%) independently of BP changes (p < 0.05). However, after Bic injection in the PVN during RNS stimulation, the BP and rSNA increased by 30% and 60% (p < 0.05), respectively, diuresis (5-fold) and natriuresis (2.3-fold) were increased (p < 0.05), and NHE3 activity was significantly reduced, independently of glomerular filtration rate changes. Thus, an acute increase in the BP overcomes RNS, leading to diuresis, natriuresis, and NHE3 activity inhibition.
Assuntos
Rim , Sódio , Ratos , Animais , Masculino , Sódio/metabolismo , Trocador 3 de Sódio-Hidrogênio , Pressão Sanguínea , Ratos Wistar , Sistema Nervoso Simpático/metabolismo , Bicuculina/farmacologiaRESUMO
Spinal cord neurons contribute to elevated sympathetic vasomotor activity in renovascular hypertension (2K1C), particularly, increased actions of angiotensin II. However, the origin of these spinal angiotensinergic inputs remains unclear. The present study aimed to investigate the role of spinal angiotensin II type 1 receptor (AT1) receptors in the sympathoexcitatory responses evoked by the activation of the rostral ventrolateral medulla (RVLM) in control and 2K1C Goldblatt rats. Hypertension was induced by clipping of the left renal artery. After 6 weeks, a catheter (PE-10) filled with losartan was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of glutamate microinjection into the RVLM on blood pressure (BP), heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated in the presence or absence of spinal AT1 blockade. Tachycardic, pressor, and renal sympathoexcitatory effects caused by RVLM activation were significantly blunted by losartan in 2K1C rats, but not in control rats. However, no differences were found in the gene expression of angiotensin-converting enzyme, angiotensinogen, and renin in the spinal cord segments between the groups. In conclusion, acute sympathoexcitation induced by RVLM activation is dependent on the spinal AT1 receptor in Goldblatt, but not in control, rats. The involvement of other central cardiovascular nuclei in spinal angiotensinergic actions, as well as the source of angiotensin II, remains to be determined in the Goldblatt model.
Assuntos
Hipertensão/fisiopatologia , Rim/inervação , Bulbo/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Medula Espinal/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Hipertensão/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Sympathetic vasomotor overactivity is a major feature leading to the cardiovascular dysfunction related to obesity. Considering that the retroperitoneal white adipose tissue (rWAT) is an important fat visceral depot and receives intense sympathetic and afferent innervations, the present study aimed to evaluate the effects evoked by bilateral rWAT denervation in obese rats. Male Wistar rats were fed with HFD for 8 consecutive weeks and rWAT denervation was performed at the 6th week. Arterial pressure, splanchnic and renal sympathetic vasomotor nerve activities were assessed and inflammation and the components of the renin -angiotensin system were evaluated in different white adipose tissue depots. HFD animals presented higher serum levels of leptin and glucose, an increase in arterial pressure and splanchnic sympathetic nerve activity; rWAT denervation, normalized these parameters. Pro-inflammatory cytokines levels were significantly increased, as well as RAAS gene expression in WAT of HFD animals; rWAT denervation significantly attenuated these changes. In conclusion, HFD promotes vasomotor sympathetic overactivation and inflammation with repercussions on the cardiovascular system. In conclusion, the neural communication between WAT and the brain is fundamental to trigger sympathetic vasomotor activation and this pathway is a possible new therapeutic target to treat obesity-associated cardiovascular dysfunction.
Assuntos
Doenças Cardiovasculares , Denervação , Dieta Hiperlipídica/efeitos adversos , Gordura Intra-Abdominal , Obesidade , Nervos Esplâncnicos , Animais , Pressão Sanguínea , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Gordura Intra-Abdominal/inervação , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Masculino , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/fisiopatologia , Obesidade/terapia , Ratos , Ratos Wistar , Sistema Renina-Angiotensina , Nervos Esplâncnicos/metabolismo , Nervos Esplâncnicos/patologia , Nervos Esplâncnicos/fisiopatologiaRESUMO
Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.
Assuntos
Vias Aferentes/fisiopatologia , Síndrome Cardiorrenal/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Rim/inervação , Insuficiência Renal Crônica/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Vias Aferentes/cirurgia , Animais , Síndrome Cardiorrenal/cirurgia , Humanos , Hipertensão Renovascular/cirurgia , Insuficiência Renal Crônica/cirurgia , Simpatectomia , Sistema Nervoso Simpático/cirurgiaRESUMO
The control of sympathetic vasomotor activity involves a complex network within the brain and spinal circuits. An extensive range of studies has indicated that sympathoexcitation is a common feature in several cardiovascular diseases and that strategies to reduce sympathetic vasomotor overactivity in such conditions can be beneficial. In the present mini-review, we present evidence supporting the spinal cord as a potential therapeutic target to mitigate sympathetic vasomotor overactivity in cardiovascular diseases, focusing mainly on the actions of spinal angiotensin II on the control of sympathetic preganglionic neuronal activity.
Assuntos
Pressão Sanguínea/fisiologia , Neurônios/fisiologia , Medula Espinal/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Frequência Cardíaca/fisiologia , Interneurônios/fisiologiaRESUMO
Previous studies have been described changes in brain regions contributing to the sympathetic vasomotor overactivity in Goldblatt hypertension (2K1C). Furthermore, changes in the spinal cord are also involved in the cardiovascular and autonomic dysfunction in renovascular hypertension, as intrathecal (i.t.) administration of Losartan (Los) causes a robust hypotensive/sympathoinhibitory response in 2K1C but not in control rats. The present study evaluated the role of spinal γ-aminobutyric acid (GABA)-ergic inputs in the control of sympathetic vasomotor activity in the 2K1C rats. Hypertension was induced by clipping the renal artery. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of i.t. injection of bicuculline (Bic) on blood pressure (BP), renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated over 40 consecutive minutes in the presence or absence of spinal AT1 antagonism. I.t. Bic triggered a more intense pressor and sympathoexcitatory response in 2K1C rats, however, these responses were attenuated by previous i.t. Los. No differences in the gene expression of GAD 65 and GABA-A receptors subunits in the spinal cord segments were found. Thus, the sympathoexcitation induced by spinal GABA-A blockade is dependent of local AT1 receptor in 2K1C but not in control rats. Excitatory angiotensinergic inputs to sympathetic preganglionic neurons are tonic controlled by spinal GABAergic actions in Goldblatt hypertension.
Assuntos
Angiotensina II/metabolismo , Hipertensão Renovascular/tratamento farmacológico , Losartan/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Masculino , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
BACKGROUND: Knowledge of the central areas involved in the control of sympathetic vasomotor activity has advanced in the last few decades. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammal nervous system, and a microinjection of bicuculline, an antagonist of GABA type A (GABA-A) receptors, into the paraventricular nucleus of the hypothalamus (PVN) alters the pattern of sympathetic activity to the renal, splanchnic and lumbar territories. However, studies are needed to clarify the role of GABAergic inputs in other central areas involved in the sympathetic vasomotor activity. The present work studied the cardiovascular effects evoked by GABAergic antagonism in the PVN, RVLM and spinal cord. METHODS AND RESULTS: Bicuculline microinjections (400 pMol in 100 nL) into the PVN and rostral ventrolateral medulla (RVLM) as well as intrathecal administration (1.6 nmol in 2 µL) evoked an increase in blood pressure, heart rate, and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), inducing a higher coherence between rSNA and sSNA patterns. However, some of these responses were more intense when the GABA-A antagonism was performed in the RVLM than when the GABA-A antagonism was performed in other regions. CONCLUSIONS: Administration of bicuculline into the RVLM, PVN and SC induced a similar pattern of renal and splanchnic sympathetic vasomotor burst discharge, characterized by a low-frequency (0.5 Hz) and high-amplitude pattern, despite different blood pressure responses. Thus, the differential control of sympathetic drive to different targets by each region is dependent, in part, on tonic GABAergic inputs.
Assuntos
Bicuculina/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/farmacologia , Medula Espinal/efeitos dos fármacos , Animais , Bicuculina/administração & dosagem , Encéfalo/metabolismo , Antagonistas de Receptores de GABA-A/administração & dosagem , Masculino , Microinjeções , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
The ablation of renal nerves, by destroying both the sympathetic and afferent fibers, has been shown to be effective in lowering blood pressure in resistant hypertensive patients. However, experimental studies have reported that the removal of sympathetic fibers may lead to side effects, such as the impairment of compensatory cardiorenal responses during a hemodynamic challenge. In the present study, we evaluated the effects of the selective removal of renal afferent fibers on arterial hypertension, renal sympathetic nerve activity, and renal changes in a model of renovascular hypertension. After 4 weeks of clipping the left renal artery, afferent renal denervation (ARD) was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of ARD, we found reduced MAP (~ 18%) and sympathoexcitation to both the ischemic and contralateral kidneys in the hypertensive group. Moreover, a reduction in reactive oxygen species was observed in the ischemic (76%) and contralateral (27%) kidneys in the 2K1C group. In addition, ARD normalized renal function markers and proteinuria and podocin in the contralateral kidney. Taken altogether, we show that the selective removal of afferent fibers is an effective method to reduce MAP and improve renal changes without compromising the function of renal sympathetic fibers in the 2K1C model. Renal afferent nerves may be a new target in neurogenic hypertension and renal dysfunction.
Assuntos
Vias Aferentes/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Isquemia/fisiopatologia , Nefropatias/fisiopatologia , Rim/fisiopatologia , Animais , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Masculino , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Ratos , Ratos Wistar , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Renal sensory activity is centrally integrated within brain nuclei involved in the control of cardiovascular function, suggesting that renal afferents regulate basal and reflex sympathetic vasomotor activity. Evidence has shown that renal deafferentation (DAx) evokes a hypotensive and sympathoinhibitory effect in experimental models of cardiovascular diseases; however, the underlying mechanisms involved in this phenomenon need to be clarified, especially those related to central aspects. We aimed to investigate the role of renal afferents in the control of γ-aminobutyric acid (GABA)ergic inputs to the paraventricular nucleus (PVN) of the hypothalamus in renovascular hypertensive (2K1C) rats and their influence in the regulation of cardiovascular function. Hypertension was induced by clipping the left renal artery. After 4 weeks, renal DAx was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of DAx, microinjection of muscimol into the PVN was performed in order to evaluate the influence of GABAergic activity in the PVN and its contribution to the control of renal sympathetic nerve activity (rSNA) and blood pressure (BP). Muscimol microinjected into the PVN triggered a higher drop in BP and rSNA in the 2K1C rats and renal DAx mitigated these responses. These results suggest that renal afferents are involved in the GABAergic changes found in the PVN of 2K1C rats. Although the functional significance of this phenomenon needs to be clarified, it is reasonable to speculate that GABAergic alterations occur to mitigate microglia activation-induced sympathoexcitation in the PVN of 2K1C rats.
RESUMO
The role of the renin-angiotensin-aldosterone system and arginine vasopressin (AVP) as humoral components in maintaining blood pressure (BP) during hemorrhagic shock (HS) is well established. However, little is known about the role of angiotensin II (Ang II) and AVP in the control of preganglionic sympathetic neuron activity. We studied the effects evoked by spinal Ang II type I (AT1) and V1a receptors antagonism on cardiovascular and sympathetic responses during HS. A catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of HS on BP, heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were analyzed in the presence or absence (HS rats) of intrathecally injected losartan (HS-Los rats) or V1a antagonist (HS-V1a rats). The right femoral artery was catheterized for bleeding. Using a 5 ml syringe, hemorrhage was maintained continuously until a BP reduction of ~50 mmHg was achieved. We found that bleeding caused a reflex increase in HR, rSNA and sSNA in the HS rats. However, such responses were attenuated in the HS-Los rats. HS-V1a rats showed a reflex increase in HR, rSNA and sSNA in terms of frequency (spikes/s) but not in amplitude. Nevertheless, the BP recovery of the groups was similar. Our data showed that spinal AT1 receptors are essential for sympathoexcitation during the acute phase of HS. Moreover, spinal AVP seems to be a neuromodulator that controls the recruitment of spinal sympathetic vasomotor neurons during the acute phase of HS.
Assuntos
Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Vasopressinas/metabolismo , Choque Hemorrágico/fisiopatologia , Medula Espinal/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Doença Aguda , Animais , Pressão Sanguínea , Frequência Cardíaca , Masculino , Ratos Wistar , Choque Hemorrágico/metabolismoRESUMO
BACKGROUND: Clinical and experimental evidence have shown that renal denervation, by removing both the sympathetic and afferent nerves, improves arterial hypertension and renal function in chronic kidney disease (CKD). Given the key role of renal sympathetic innervation in maintaining sodium and water homeostasis, studies have indicated that the total removal of renal nerves leads to impaired compensatory mechanisms during hemodynamic challenges. METHOD: In the present study, we hypothesized that afferent (or sensory) fibers from the diseased kidney contribute to sympathetic overactivation to the kidney and other target organ, such as the splanchnic region, contributing to hypertension in CKD. We used a method to remove selectively the afferent renal fibers (periaxonal application of 33âmmol/l capsaicin) in a rat model of CKD, the 5/6 nephrectomy. RESULTS: Three weeks after afferent renal denervation (ARD), we found a decrease in mean arterial pressure (â¼15%) and normalization in renal and splanchnic sympathetic nerve hyperactivity in the CKD group. Interestingly, intrarenal renin--angiotensin system, as well as renal fibrosis and function and proteinuria were improved after ARD in CKD rats. CONCLUSION: The findings demonstrate that afferent fibers contribute to the maintenance of arterial hypertension and reduced renal function that are likely to be mediated by increased sympathetic nerve activity to the renal territory as well as to other target organs in CKD.
Assuntos
Pressão Arterial/fisiologia , Denervação/métodos , Hipertensão Renal/cirurgia , Rim/inervação , Insuficiência Renal Crônica/cirurgia , Sistema Nervoso Simpático/fisiopatologia , Animais , Hipertensão Renal/fisiopatologia , Rim/fisiopatologia , Masculino , Ratos , Insuficiência Renal Crônica/fisiopatologiaRESUMO
We aimed to investigate the effects of nitric oxide (NO) synthesis inhibition by NO synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) treatment on the sympathetic vasomotor nerve activity (SNA) on two sympathetic vasomotor nerves, the renal and splanchnic. NO plasma level and systemic oxidative stress were assessed. Hypertension was induced by L-NAME (20 mg/kg per day, by gavage, for seven consecutive days) in male Wistar rats. At the end of the treatment, blood pressure, heart rate, arterial baroreflex sensitivity, renal SNA (rSNA), and splanchnic SNA (sSNA) were assessed in urethane anesthetized rats. L-NAME-treated rats presented increased blood pressure (152 ± 2 mmHg, n = 17) compared to the control group (101 ± 2 mmHg, n = 15). Both rSNA (147 ± 10, n = 15 vs. 114 ± 5 Spikes/s, n = 9) and sSNA (137 ± 13, n = 14 vs. 74 ± 13 spikes/s, n = 9) were significantly increased in the L-NAME-treated compared to the control group. A differential response on baroreflex sensitivity was found, with a significant reduction for rSNA but not for sSNA arterial baroreceptor sensitivity in L-NAME-treated rats. The adjusted regression model revealed that the reduction of systemic NO levels partially explains the variation in sSNA and blood pressure, but not rSNA. Taken together, our data show that hypertension induced by NO synthase blockade is characterized by increased SNA to the rSNA and sSNA. In addition, we found that the rats that had the greatest reduction in NO levels in plasma by L-NAME were those that developed higher blood pressure levels. The reduction in the NO level partially explains the variations in sSNA but not in rSNA.
Assuntos
Barorreflexo , Hipertensão/fisiopatologia , Óxido Nítrico Sintase/antagonistas & inibidores , Sistema Nervoso Simpático/fisiopatologia , Vasoconstrição , Animais , Pressão Sanguínea , Inibidores Enzimáticos/toxicidade , Hipertensão/etiologia , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Óxido Nítrico/sangue , Ratos , Ratos WistarRESUMO
Sympathetic overactivation contributes to the pathogenesis of both experimental and human hypertension. We have previously reported that oxidative stress in sympathetic premotor neurons leads to arterial baroreflex dysfunction and increased sympathetic drive to the kidneys in an experimental model of neurogenic hypertension. In this study, we hypothesized that melatonin, a potent antioxidant, may be protective in the brainstem regions involved in the tonic and reflex control of blood pressure (BP) in renovascular hypertensive rats. Neurogenic hypertension was induced by placing a silver clip (gap of 0.2 mm) around the left renal artery, and after 5 weeks of renal clip placement, the rats were treated orally with melatonin (30 mg/kg/day) by gavage for 15 days. At the end of melatonin treatment, we evaluated baseline mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), and the baroreflex control of heart rate (HR) and rSNA. Reactive oxygen species (ROS) were detected within the brainstem regions by dihydroethidium staining. Melatonin treatment effectively reduced baseline MAP and sympathoexcitation to the ischemic kidney in renovascular hypertensive rats. The baroreflex control of HR and rSNA were improved after melatonin treatment in the hypertensive group. Moreover, there was a preferential decrease in ROS within the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). Therefore, our study indicates that melatonin is effective in reducing renal sympathetic overactivity associated with decreased ROS in brainstem regions that regulate BP in an experimental model of neurogenic hypertension.
Assuntos
Antioxidantes/uso terapêutico , Barorreflexo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Hipertensão Renovascular/tratamento farmacológico , Melatonina/uso terapêutico , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Masculino , Melatonina/farmacologia , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Pre-eclampsia (PE) affects approximately 2 to 8% of pregnant women, causing blood pressure above 140 × 90 mmHg and proteinuria, normally after the 20th gestation week. If unsuccessfully treated, PE can lead to self-limited seizures (Eclampsia) that could eventually result in death of the mother and her fetus. The present study reports an experimental model of preeclampsia hypertension in pregnant (HP) and non-pregnant (H) Wistar rats by partially clamping one of their renal arteries. Pregnant (P) and non-pregnant (C) controls were provided. Differently from controls (C and P), H and HP animals presented a steady rise in BP two weeks after renal artery clamping. Injection of pentylenetetrazol (PTZ) induced behavioral and electroencephalographic seizures in all groups, which were increased in number, duration, amplitude and power accompanied by decreased latency in HP animals (p < 0.05). Consistent results were obtained in in vitro experimentation. Immunohistochemistry of hippocampus tissue in HP animals showed decreased density of neurons nuclei in CA1, CA3 and Hilus and increased density of astrocytes in CA1, CA3 and gyrus (p < 0.05). The present findings show that the clamping of one renal arteries to 0.15 mm and PTZ administration were able to induce signs similar to human PE in pregnant Wistar rats.
Assuntos
Pressão Sanguínea , Hipertensão/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Feto , Hipocampo/diagnóstico por imagem , Hipocampo/fisiopatologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/etiologia , Pré-Eclâmpsia/diagnóstico por imagem , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Ratos , Ratos Wistar , Artéria Renal/diagnóstico por imagem , Artéria Renal/fisiopatologiaRESUMO
The underlying mechanisms by which renal denervation (RD) decreases blood pressure (BP) remain incompletely understood. In this study, we investigated the effects of ischemic kidney denervation on different sympathetic outflows, brain and renal expression of angiotensin-II receptors, oxidative stress and renal function markers in the 2-kidney, 1-clip (2K-1C) rat model. Surgical RD was performed in Wistar male rats 4-5 weeks after clip implantation. After 10 days of RD, BP, and the activity of sympathetic nerves projecting to the contralateral kidney (rSNA) and splanchnic region were partially reduced in 2K-1C rats, with no change in systemic renin-angiotensin system (RAS). To distinguish the effects of RD from the reduction in BP, 2K-1C rats were treated with hydralazine by oral gavage (25 mg/kg/day for 1 week). RD, but not hydralazine, normalized oxidative stress in the sympathetic premotor brain regions and improved intrarenal RAS, renal injury, and proteinuria. Furthermore, different mechanisms led to renal injury and oxidative stress in the ischemic and contralateral kidneys of 2K-1C rats. Injury and oxidative stress in the ischemic kidney were driven by the renal nerves. Although RD attenuated rSNA, injury and oxidative stress persisted in the contralateral kidney, probably due to increased BP. Therefore, nerves from the ischemic kidney at least partially contribute to the increase in BP, sympathetic outflows, brain oxidative stress, and renal alterations in rats with renovascular hypertension. Based on these findings, the reduction in oxidative stress in the brain is a central mechanism that contributes to the effects of RD on Goldblatt hypertension.
Assuntos
Denervação , Hipertensão Renovascular/cirurgia , Rim/inervação , Estresse Oxidativo , Núcleo Hipotalâmico Paraventricular/metabolismo , Animais , Pressão Sanguínea , Hidralazina , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Rim/fisiopatologia , Masculino , NADPH Oxidases/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de Angiotensina/metabolismoRESUMO
Aging immune deterioration and Epstein-Barr (EBV) intrinsic mechanisms play an essential role in EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV + DLBCLe) pathogenesis, through the expression of viral proteins, interaction with host molecules and epigenetic regulation, such as miR-155, required for induction of M1 phenotype of macrophages. This study aims to evaluate the relationship between macrophage polarization pattern in the tumor microenvironment and relative expression of miR-155 in EBV + DLBCLe and EBV-negative DLBCL patients. We studied 28 EBV + DLBCLe and 65 EBV-negative DLBCL patients. Tumor-associated macrophages (TAM) were evaluated by expression of CD68, CD163 and CD163/CD68 ratio (degree of M2 polarization), using tissue microarray. RNA was extracted from paraffin-embedded tumor samples for miR-155 relative expression study. We found a significantly higher CD163/CD68 ratio in EBV + DLBCLe compared to EBV-negative DLBCL. In EBV-negative DLBCL, CD163/CD68 ratio was higher among advanced-staged/high-tumor burden disease and overexpression of miR-155 was associated with decreased polarization to the M2 phenotype of macrophages. The opposite was observed in EBV + DLBCLe patients: we found a positive association between miR-155 relative expression and CD163/CD68 ratio, which was not significant after outlier exclusion. We believe that the higher CD163/CD68 ratio in this group is probably due to the presence of the EBV since it directly affects macrophage polarization towards M2 phenotype through cytokine secretion in the tumor microenvironment. Therapeutic strategies modulating miR-155 expression or preventing immuno-regulatory and pro-tumor macrophage polarization could be adjuvants in EBV + DLBCLe therapy since this entity has a rich infiltration of M2 macrophages in its tumor microenvironment.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/imunologia , Antígenos de Diferenciação Mielomonocítica/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/fisiologia , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/genética , Ativação de Macrófagos/imunologia , Macrófagos/classificação , Macrófagos/metabolismo , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: -8⯱â¯3 vs. -52⯱â¯9 spikes/s after 120'). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80' after administration (CTL vs. 2K1C - 80â¯min: -10⯱â¯2 vs. -32⯱â¯6∗; 100â¯min: -15⯱â¯4 vs. -37⯱â¯9∗; 120â¯min: -12⯱â¯5 vs. -37⯱â¯8∗ spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.
Assuntos
Hipertensão Renovascular/fisiopatologia , Rim/efeitos dos fármacos , Medula Espinal/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Fármacos Atuantes sobre Aminoácidos Excitatórios/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/metabolismo , Rim/inervação , Ácido Cinurênico/farmacologia , Losartan/farmacologia , Masculino , Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Sympathetic vasomotor activity is significantly increased in renovascular hypertension. Renal denervation (DnX) has emerged as a novel therapy for resistant hypertension to drug therapy. However, the underlying mechanisms regarding the reduction in blood pressure (BP) after DnX remain unclear. Thus, the aim of this study was to evaluate the effects of DnX of a clipped kidney on the baseline and baroreceptor reflex control of post-ganglionic sympathetic activity to the contralateral kidney (rSNA) and lumbar (lSNA) nerves in Goldblatt hypertensive rats (2K1C). Renal denervation of an ischaemic kidney (DxX - all visible bundles of nerves were dissected - 10% phenol) was performed 5weeks after clipping (gap width: 0.2mm). Ten days after DnX, BP was significantly reduced (16%) in the 2K1C compared with the undenervated 2K1C (p<0.05). DnX significantly reduced basal rSNA (control group (CT): 110±8, n=14; 2K1C: 150±8, n=12; 2K1C DnX: 89±7, spikes per second (spikes/s); p<0.05, n=8) and lSNA (CT: 137±8, n=8; 2K1C: 202±7, n=11; 2K1C DnX: 131±7, spikes/s; p<0.05, n=8) only in 2K1C rats. DnX significantly improved the arterial baroreceptor sensitivity of rSNA (CT: -2.3±0.2, n=11; 2K1C: -0.7±0.1, n=8; 2K1C DnX: -1.5±0.2, spikes/s/mmHg; p<0.05, n=5) and heart rate for tachycardic response (CT: -3.9±0.5, n=7; 2K1C: -1.9±0.1, n=8; 2K1C DnX: -3.3±0.4, bpm/mmHg; p<0.05, n=8), but not for lSNA in 2K1C rats. The results show that DnX normalized baseline sympathetic vasomotor activity to the lumbar and renal nerves, followed by a differential improvement in the arterial baroreceptor sensitivity. Whether the baroreceptor function sensitivity improvement induced by DnX is a cause or a consequence of BP reduction remains to be determined.