RESUMEN
PURPOSE: To test a new approach to address moral distress in intensive care unit (ICU) personnel. METHODS: Using principles of participatory action research, we developed an eight-step moral conflict assessment (MCA) that guides participants in describing the behaviour that they have to implement, the effects this has on them, their current coping strategies, their values in conflict, any other concerns related to the situation, what helps and hinders the situation, new coping strategies, and the effect of the preceding steps on participants. This assessment was tested with eight ICU providers in an 11-bed community ICU. RESULTS: During three one-hour sessions, participants described their moral distress that was caused by the use of ongoing life-support for a patient who the team believed did not prefer this course of care, but whose family was requesting it. Participants experienced frustration and discouragement and coping strategies included speaking to colleagues and exercising. They felt that they were unable to take meaningful action to resolve this conflict. Values that were in conflict in the situation included beneficence and patient autonomy. Based on ranking of helping and hindering factors, the team proposed new strategies including improving consistency of care plans and educating patients' family members and ICU personnel about advance care planning and end-of-life care. After completing this assessment, participants reported less stress and a greater ability to take meaningful action, including some of the proposed new strategies. CONCLUSIONS: We found this new approach to address moral distress in ICU personnel to be feasible and a useful tool for facilitating plans for reducing moral distress.
RéSUMé: OBJECTIF: Nous avons souhaité mettre à l'essai une nouvelle approche pour traiter la détresse morale du personnel des unités de soins intensifs (USI). MéTHODE: En nous fondant sur les principes de la recherche-action participative, nous avons développé une évaluation des conflits moraux (ECM) en huit étapes qui guide les participants dans la description du comportement qu'ils doivent mettre en Åuvre, des effets que cela a sur eux, de leurs stratégies d'adaptation actuelles, de leurs valeurs en conflit, de toute autre préoccupation liée à la situation, de ce qui aide et entrave la situation, de nouvelles stratégies d'adaptation, et de l'effet des étapes précédentes sur les participants. Cette évaluation a été testée auprès de huit praticiens de soins intensifs dans une unité de soins intensifs communautaire de 11 lits. RéSULTATS: Au cours de trois séances d'une heure, les participants ont décrit leur détresse morale causée par l'utilisation d'un système de réanimation continu pour un patient qui, selon l'équipe, ne préférait pas ce traitement, mais qui était demandé par la famille. Les participants ont éprouvé de la frustration et du découragement et les stratégies d'adaptation comprenaient le fait d'en parler à des collègues et de faire de l'exercice. Ils se sont sentis incapables de poser des gestes significatifs pour résoudre ce conflit. Les valeurs qui étaient en conflit dans la situation comprenaient la bienfaisance et l'autonomie du patient. Sur la base du classement des facteurs d'aide et d'entrave, l'équipe a proposé de nouvelles stratégies, notamment l'amélioration de l'uniformité des plans de soins et l'éducation des membres de la famille des patients et du personnel des soins intensifs sur la planification de soins avancés et les soins de fin de vie. Après avoir terminé cette évaluation, les participants ont déclaré éprouver moins de stress et une plus grande capacité à poser des gestes significatifs, y compris certaines des nouvelles stratégies proposées. CONCLUSION: Nous avons constaté que cette nouvelle approche visant à traiter la détresse morale chez le personnel des soins intensifs était faisable et qu'elle constituait un outil utile pour faciliter les plans de réduction de la détresse morale.
Asunto(s)
Estrés Psicológico , Cuidado Terminal , Adaptación Psicológica , Actitud del Personal de Salud , Humanos , Unidades de Cuidados Intensivos , Principios Morales , Encuestas y CuestionariosRESUMEN
The need for a change away from classical nucleation and growth models for the description of nanoparticle formation is highlighted. By the use of in situ total X-ray scattering experiments the transformation of an aqueous polyoxometalate precursor mixture to crystalline ZnWO4 nanoparticles under hydrothermal conditions was followed. The precursor solution is shown to consist of specific Tourné-type sandwich complexes. The formation of pristine ZnWO4 within seconds is understood on the basis of local restructuring and three-dimensional reordering preceding the emergence of long range order in ZnWO4 nanoparticles. An observed temperature dependent trend in defect concentration can be rationalized based on the proposed formation mechanism. Following nucleation the individual crystallites were found to grow into prolate morphology with elongation along the unit cell c-direction. Extensive electron microscopy characterization provided evidence for particle growth by oriented attachment; a notion supported by sudden particle size increases observed in the in situ total scattering experiments. A simple continuous hydrothermal flow method was devised to synthesize highly crystalline monoclinic zinc tungstate (ZnWO4) nanoparticles in large scale in less than one minute. The present results highlight the profound influence of structural similarities in local structure between reactants and final materials in determining the specific nucleation of nanostructures and thus explains the potential success of a given synthesis procedure in producing nanocrystals. It demonstrates the need for abolishing outdated nucleation models, which ignore subtle yet highly important system dependent differences in the chemistry of the forming nanocrystals.
RESUMEN
Mesangial matrix expansion is an early lesion leading to glomeruloclerosis and chronic renal diseases. A beneficial effect is achieved with angiotensin I-converting enzyme inhibitors (ACEI), which also favor bradykinin (BK) B2 receptor (B2R) activation. To define the underlying mechanism, we hypothesized that B2R activation could be a negative regulator of collagen synthesis in mesangial cells (MC). We investigated the effect of BK on collagen synthesis and signaling in MC. Inflammation was evaluated by intercellular adhesion molecule-1 (ICAM-1) expression. BK inhibited collagen I and IV synthesis stimulated by high glucose, epithelial growth factor (EGF), and transforming growth factor-ß (TGF-ß) but did not alter ICAM-1. Inhibition of collagen synthesis was B2R but not B1R mediated. PKC or phosphatidylinositol 3-kinase (PI3K) inhibitors mimicked the BK effect. B2R activation inhibited TGF-ß- and EGF-induced Erk1/2, Smad2/3, Akt S473, and EGFR phosphorylation. A phosphatase inhibitor prevented BK effects. The in vivo impact of B2R on mesangial matrix expansion was assessed in streptozotocin-diabetic rodents. Deletion of B2R increased mesangial matrix expansion and albuminuria in diabetic mice. In diabetic rats, matrix expansion and albuminuria were prevented by ACEI but not by ACEI and B2R antagonist cotreatment. Consistently, the lowered BK content of diabetic glomeruli was restored by ACEI. In conclusion, deficient B2R activation aggravated mesangial matrix expansion in diabetic rodents whereas B2R activation reduced MC collagen synthesis by a mechanism targeting Erk1/2 and Akt, common pathways activated by EGF and TGF-ß. Taken together, the data support the hypothesis of an antifibrosing effect of B2R activation.
Asunto(s)
Bradiquinina/farmacología , Colágeno Tipo IV/antagonistas & inhibidores , Colágeno Tipo I/antagonistas & inhibidores , Factor de Crecimiento Epidérmico/farmacología , Glucosa/farmacología , Células Mesangiales/efectos de los fármacos , Células Mesangiales/metabolismo , Receptor de Bradiquinina B2/metabolismo , Animales , Células Cultivadas , Colágeno Tipo I/metabolismo , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Molécula 1 de Adhesión Intercelular/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/fisiología , Ratas , Ratas Sprague-Dawley , Receptor de Bradiquinina B2/deficiencia , Receptor de Bradiquinina B2/genética , Transducción de Señal/fisiología , Estreptozocina/efectos adversos , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
BACKGROUND: To evaluate the long-term results in a multicentric continuous series of narrowing lesions of the aortic bifurcation treated with a kissing stent. METHODS: From January, 1st 1999 to the December, 31st 2001, all of the patients (n = 80) presenting with stenosis of the aortic bifurcation (n = 15) and/or the 2 common iliac arteries (n = 65), treated with a kissing stent, in 8 teaching hospitals were collected retrospectively. The risk factors were smoking (91%), dyslipidemia (60%), arterial hypertension (42%) and diabetes (27%). In 84% of cases, the indication for treatment was claudication. The lesions were stenotic < 70% (n = 76) and/or thrombotic (n = 18). The associated lesions were external iliac stenoses (n = 21), common femoral stenoses (n = 19), femoro-popliteal stenoses (n = 42), arteriopathy in the leg (n = 35). Follow-up was clinical examination and Doppler US scan. RESULTS: The success rate of the technique was 89%. There were 4 cases (5.3%) of residual stenosis and 4 cases (5.3%) of dissection. The length of the lesions treated in the aorta and the iliac arteries was respectively 17.1 ± 7 and 17.3 ± 9 mm. The stents were all placed as kissing stents, and had a mean diameter and a mean length of 13.75 mm and 56 mm in the aorta and 9 mm and 48 mm in the iliac arteries, respectively. At 5 years, 19 patients had required repeat angioplasty in the treated area, and 13 had undergone open surgery. Primary and assisted primary patency at 5 years were 64.5% and 81.8%, respectively. CONCLUSION: Long-term follow-up of endovascular treatment with kissing stents for stenosis of the aortic bifurcation shows that this technique gives good results, though it does not justify doing away with classical revascularisation surgery, in a population with major cardiovascular risk factors.
Asunto(s)
Aorta Abdominal , Arteriopatías Oclusivas/cirugía , Implantación de Prótesis Vascular/métodos , Arteria Femoral , Arteria Ilíaca , Stents , Arteriopatías Oclusivas/diagnóstico , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Moldes Quirúrgicos/efectos adversos , Inmovilización/efectos adversos , Enfermeras Clínicas/organización & administración , Rol de la Enfermera , Enfermería Ortopédica/organización & administración , Humanos , Enfermeras Clínicas/educación , Enfermería Ortopédica/educación , Educación del Paciente como AsuntoRESUMEN
BACKGROUND: Although ionizing radiation has been proposed for the prevention of intimal hyperplasia in coronary and peripheral arteries in multicenter clinical trials, information is lacking on how irradiation affects arterial histology after stenting and especially how it affects the edges of the stent. We investigated intimal hyperplasia recasting with histological changes in arterial wall at the edges of the stent after arterial stenting followed by adequate external radiation for the prevention of intimal hyperplasia in pigs. MATERIALS AND METHODS: The aorta was experimentally stented in 30 pigs who were then assigned to two groups: irradiation with 20 Gy and a control group with no irradiation. The aorta was resected for morphometric and histological studies 6 weeks after procedure. RESULTS: Intimal thickness was reduced and the intima/media ratio was significantly lower in irradiated groups than in control pigs. In the irradiated group histological examination at the edges of the stent showed thin neointimal proliferation with an intact endothelium. In all sections analyzed in the 20-Gy irradiated group the vascular media at 45 days contained necrotic areas and fibrosis with calcifications. CONCLUSIONS: After arterial injury, adequate ionizing radiation effectively reduces neointimal thickening. Irradiation-induced histological changes include previously undetected recasting with necrosis and fibrosis at the arterial edges of the stent. The parietal recasting we observed in animal arteries irradiated at high doses is unclear and a cause of concern especially after clinical spontaneous dissection was recently reported. The use of ionizing radiation for the prevention of arterial restenosis awaits confirmation with a long-term follow-up including specific experimental histological analyses.
Asunto(s)
Arterias/patología , Arterias/efectos de la radiación , Stents/efectos adversos , Animales , Femenino , Hiperplasia/prevención & control , Hiperplasia/radioterapia , Inmunohistoquímica , Radiación Ionizante , Estadísticas no Paramétricas , Sus scrofaRESUMEN
BACKGROUND: Although ionizing radiation has been proposed for the prevention of intimal hyperplasia in coronary and peripheral arteries, information is lacking on how irradiation affects arterial histology and neointimal smooth-muscle cell proliferation-the hallmark of restenosis. We chronologically investigated early histological changes and quantitative changes in arterial wall cell proliferation after arterial injury followed by external radiation for the prevention of intimal hyperplasia in rabbits. MATERIALS AND METHODS: The aorta was experimentally injured in 26 rabbits who were then assigned to two groups: irradiation with 20 Gy and a control group with no irradiation. The aorta was resected for morphometric and histological studies at 3, 7, 15, 30, and 45 days after experimental injury. RESULTS: Intimal thickness was reduced and the intima/media ratio was significantly lower in irradiated groups than in control rabbits. In the irradiated group histological examination showed delayed neointimal proliferation with an intact endothelium. In the 20-Gy irradiated group the vascular media at 7 days contained necrotic areas and delayed fibrosis with calcifications. There was no statistical difference between the number of proliferating cells in the irradiated groups and the control group. Proliferating cells reached maximum numbers later in irradiated groups than in control rabbits (45 days versus 3 days). CONCLUSION: After arterial injury, external irradiation at 20 Gy effectively reduced aortic neointimal thickening. Irradiation-induced histological changes include recasting with rapid necrosis and delayed fibrosis. Radiation-induced parietal recasting with necrosis, fibrosis, and calcifications might worsen in time. Although irradiation after arterial injury leaves proliferative smooth-muscle cells within the arterial wall quantitatively unchanged in the early days after the procedure, it then induces a delayed reaction (observed over 45 days in our study). Whether neointimal hyperplasia is merely delayed or will ultimately develop causing restenosis awaits confirmation from experimental and clinical studies with a long-term follow-up.
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Aorta/patología , Aorta/efectos de la radiación , Radiación Ionizante , Túnica Íntima/patología , Animales , Aorta/lesiones , Cateterismo/efectos adversos , Proliferación Celular/efectos de la radiación , Femenino , Hiperplasia/etiología , Hiperplasia/prevención & control , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Conejos , Factores de TiempoRESUMEN
Some combinations of antihypertensive agents were shown to reduce proteinuria in patients with renal failure. However, preventive effects of such combinations on renal structure and function are presently unknown when treatment is administered before the onset of renal abnormalities. We thus investigated the long-term effects of an angiotensin-converting enzyme (ACE) inhibitor (perindopril)/diuretic (indapamide) combination (per/ind) in the Zucker rat, a classical model of chronic renal failure associated with obesity, hyperlipidemia, and insulin resistance. Two-month-old lean and obese Zucker rats, presenting normal renal structure and function at this young age, received per/ind (0.76 + 0.24 mg/kg of body weight/day) or the vehicle of this combination by daily gavage. After 8.5 consecutive months of treatment, those 10.5-month-old rats were used for determination of renal structural and functional parameters which were examined using standard renal clearance experiments and kidney tissue analysis. Per/ind prevented focal and segmental glomerular hyalinosis and tubulo-interstitial damage in obese rats. Treatment was also associated with a significant reduction in several staining markers of glomerular and interstitial fibrosis. The hypertrophy of superficial glomeruli and the mesangial expansion of deep glomeruli observed in control rats were reduced in per/ind-treated obese rats. The severe proteinuria observed in 10.5-month-old control obese rats was prevented by per/ind, while glomerular filtration and renal hemodynamic parameters reached similar values to those obtained in lean animals. These results show that long-term treatment with this ACE inhibitor/diuretic combination protects renal structure and function in the obese Zucker rat, emphasizing the potential efficiency of such therapy in renal failure prevention.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Diuréticos/uso terapéutico , Indapamida/uso terapéutico , Perindopril/uso terapéutico , Proteinuria/prevención & control , Insuficiencia Renal/prevención & control , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Animales , Diuréticos/administración & dosificación , Diuréticos/farmacocinética , Combinación de Medicamentos , Fibrosis/prevención & control , Indapamida/administración & dosificación , Indapamida/farmacocinética , Pruebas de Función Renal , Masculino , Tasa de Depuración Metabólica , Obesidad/complicaciones , Perindopril/administración & dosificación , Perindopril/farmacocinética , Proteinuria/etiología , Ratas , Ratas Zucker , Insuficiencia Renal/etiología , Insuficiencia Renal/patologíaRESUMEN
In recent years there has been intensive research on the use of ionizing radiation for inhibition of intimal hyperplasia (IH). Results have clearly established that beta ionizing radiation delivered from an endoluminal source after angioplasty inhibits intimal restenosis. This effect has been confirmed by recent multicenter clinical trials in patients undergoing coronary dilatation. The purpose of this study was to determine if gamma radiation therapy delivered superficially from an external source also reduced smooth muscle cell proliferation in two animals models-the first involving experimentally induced restenosis and the second involving anastomosis between a prosthesis and artery. Ultimately we hope to develop a therapeutic application for patients undergoing peripheral anastomoses, especially in the lower extremities. Two different animal models were used in this two-stage study. The first-stage rabbit model (model 1) involved balloon injury of the aorta to validate the dose effect of external beam irradiation. The second-stage porcine model (model 2) involved aortic bypass followed by external beam irradiation of the distal anastomosis site. In model 1 a total of 56 rabbits were studied. They were divided into five groups including one control group in which external radiation was not applied after balloon injury and four test groups in which external radiation was applied in a single fraction on day 0 at four different doses: 10 grays, 15 grays, 20 grays, and 25 grays. In model 2, a total of 24 pigs underwent aortic bypass with a 6-mm PTFE graft followed by irradiation of the distal end-to-side anastomosis at a dose of 20 grays on day 0. In both models specimens were harvested after 6 weeks and studied histologically after staining with HES and orcein, histomorphometrically by measuring intimal hyperplasia, and immunohistochemically using actin and factor VIII/von Willebrand factor (F VIII/vWF). The zones of study on the anastomosis were separated into base of the artery to the tip and heel of the anastomosis and the edge of the arteriotomy. Measurements were compared using the Mann Whitney test. In the first-stage model designed to study IH in rabbits, mean intimal and medial thickness values and the intima-to-media ratio showed no difference between the control group and the groups irradiated at doses of 10 grays and 15 grays (p = 0.111, p = 0.405, and p = 0.14); (p = 0.301, p = 0.206, and p = 0.199). Conversely, there was a significant difference between the control group and the groups irradiated at 20 grays and 25 grays (p < 0.0001, p = 0.107 and p = 0.008; p = 0.008, p = 0.155, and p = 0.008). Histological examination demonstrated extensive changes in the wall with high-grade fibrosis after application of ionizing radiation. In the second-stage swine model, irradiation significantly inhibited development of IH at the level of anastomosis both at the base of the artery (p < 0.01) (tip 0.06 vs. 0.27 mm and heel 0.04 vs. 0.36) and at the level of the arteriotomy at the suture site (p < 0.001) (0.13 vs. 0.86 mm). Immunochemical analysis of the thickened zones showed a positive reaction of endothelial cells to smooth muscle actin and F VII/vWF. Like irradiation applied using an endoluminal source, superficial gamma ionizing radiation from an external source inhibits IH. Analysis of the dose effect showed that the overall dose must be between 15 and 20 grays. External radiation also reduces overall IH at the anastomosis between a prosthesis and artery. Although these experimental data are promising, further study will probably be necessary before attempting to undertake clinical trials using external beam radiation therapy for patients undergoing peripheral anastomoses.
Asunto(s)
Aorta/efectos de la radiación , Implantación de Prótesis Vascular/efectos adversos , Cateterismo/efectos adversos , Radioterapia/métodos , Túnica Íntima/efectos de la radiación , Animales , Aorta/patología , Materiales Biocompatibles/efectos adversos , Prótesis Vascular/efectos adversos , Constricción Patológica/radioterapia , Hiperplasia/radioterapia , Modelos Animales , Músculo Liso Vascular/patología , Músculo Liso Vascular/efectos de la radiación , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/efectos de la radiación , Politetrafluoroetileno/efectos adversos , Conejos , Recurrencia , Porcinos , Túnica Íntima/patologíaRESUMEN
Chronic renal failure often induces left ventricular hypertrophy. We assessed whether the heart is affected in the Zucker obese rat, a model of chronic renal failure associated with obesity, glucose intolerance, and insulin resistance without hypertension or hyperglycemia. After systemic blood pressure measurement, the heart, the aorta, and the kidneys were removed from anesthetized 9- and 13-mo-old Zucker obese and lean control male rats (n = 33, n = 24, n = 25, and n = 21, respectively). Determination of left ventricular geometry, quantification of myocardium collagen density, and measurement of heart antioxidant enzyme activity were made, as well as aorta and kidney parameters. Mean blood pressure remained at a normal range whatever the age and group considered. Whereas kidney structure and function were severely impaired, no sign of myocardial infarction or inflammatory process was noticed. A moderate left ventricular hypertrophy was observed in 13-mo-old obese rats. While heart malondialdehyde was stable with age and among groups, antioxidant enzyme activity was higher in obese rats. In conclusion, in the absence of hypertensive or hyperglycemic disorders, the heat seems to display a sufficient line of defense against oxidative stress during the development of cardiac hypertrophy.
Asunto(s)
Envejecimiento/metabolismo , Antioxidantes/metabolismo , Miocardio/metabolismo , Obesidad/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/fisiología , Colágeno/metabolismo , Vasos Coronarios/patología , Glutatión/metabolismo , Ventrículos Cardíacos/patología , Hemodinámica/fisiología , Inmunohistoquímica , Pruebas de Función Renal , Peroxidación de Lípido/fisiología , Masculino , Malondialdehído/metabolismo , Miocardio/patología , Obesidad/genética , Obesidad/patología , Tamaño de los Órganos/fisiología , Estrés Oxidativo/fisiología , Ratas , Ratas ZuckerRESUMEN
Bradykinin B(2) receptor knockout mice (B(2)-/-) have been useful to study the role of bradykinin under pathological conditions. With the use of these mice, it was shown that bradykinin plays an important role in angiogenesis, heart failure, salt-induced hypertension, and kidney fibrosis. Data on the role of the bradykinin B(2) receptor under physiological conditions using these mice are controversial and scarce, because these mice have no typical phenotype. For this reason, we have studied, under physiological conditions, renal hemodynamics as well as a number of morphometric glomerular parameters of B(2)-/- mice on a homogenized genetic background and on mice bred in a pathogen-free environment. Backcrossed B(2)-/- mice had normal blood pressure and normal apparent renal hemodynamics and morphology. However, reduced renal nitrite excretion and glomerular cGMP content were found, which was associated with a reduced glomerular capillary surface area. These differences had, however, no detectable effects on renal hemodynamics. These differences between B(2)-/- and wild-type mice might become important under pathological conditions as shown by a number of studies using these bradykinin B(2) receptor knockout mice.
Asunto(s)
Glomérulos Renales/anatomía & histología , Riñón/metabolismo , Óxido Nítrico/orina , Receptores de Bradiquinina/fisiología , Animales , Presión Sanguínea/genética , Presión Sanguínea/fisiología , GMP Cíclico/metabolismo , Tasa de Filtración Glomerular/genética , Tasa de Filtración Glomerular/fisiología , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Hemodinámica/genética , Hemodinámica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Repeticiones de Microsatélite , Receptor de Bradiquinina B2 , Receptores de Bradiquinina/genética , Circulación Renal/genética , Resistencia Vascular/genética , Resistencia Vascular/fisiologíaRESUMEN
OBJECTIVE: To correlate the susceptibility of low-(LDL) and very-low-density lipoprotein to oxidation in vitro and the concentrations of serum antibodies against malondialdehyde-modified LDL and plasma vitamin E with the anthropometric and laboratory characteristics of obesity. RESEARCH METHODS AND PROCEDURES: A total of 75 nondiabetic, normotensive obese patients were assigned to one of four groups according to their body mass index (BMI): moderately obese (30 Asunto(s)
Peroxidación de Lípido
, Obesidad/sangre
, Vitamina E/sangre
, Adulto
, Consumo de Bebidas Alcohólicas
, Anticuerpos/sangre
, Constitución Corporal
, Índice de Masa Corporal
, Colesterol/sangre
, Cobre/química
, Femenino
, Humanos
, Lipoproteínas LDL/sangre
, Lipoproteínas LDL/inmunología
, Lipoproteínas VLDL/sangre
, Masculino
, Malondialdehído/farmacología
, Persona de Mediana Edad
, Obesidad Mórbida/sangre
, Fumar
, Triglicéridos/sangre
RESUMEN
BACKGROUND: The beneficial effects of therapeutic angiotensin-converting enzyme (ACE) inhibitor treatment against the worsening of glomerulosclerosis during the course of diabetic nephropathy have been widely documented. ACE inhibitors inhibit both angiotensin II formation and bradykinin (BK) degradation, thereby reducing angiotensin II type 1 (AT1) receptor activity and favoring B2-kinin receptor (B2 receptor) activation. Since the involvement of growth factors such as insulin-like growth factor (IGF-I) has been implicated in the early steps of diabetic nephropathy, we investigated the effect of BK on Erk 1 and 2 activation and cell proliferation by IGF-I. METHODS: The activation of Erk 1 and 2 in mesangial cells (MCs) and isolated glomeruli (IG) was investigated by immunoprecipitation and Western blotting during activation of the IGF-I receptor in the presence or absence of BK and of protein kinase C (PKC), tyrosine-kinase and phosphatase selective inhibitors. Mesangial cell proliferation was assessed in vitro by cell counting. RESULTS: In untreated MCs and IG, when added separately, BK and IGF-I both activated Erk 1 and 2. In contrast, in MCs and IG pretreated with BK, the IGF-I-induced Erk 1 and 2 activation was dose-dependently reduced. The inhibitory effect of BK on IGF-I-induced activation of Erk 1 and 2 was completely abolished by addition of a B2 antagonist, by chelation of intracellular calcium and by tyrosine phosphatase inhibition. Additionally, BK reduced MC proliferation induced by IGF-I. CONCLUSIONS: A new inhibitory pathway of the early steps of IGF-I signaling by the B2 receptor is found both in cultured MCs and in IG, which involves a calcium-dependent tyrosine phosphatase activity. Recruitment of this mechanism may account for the beneficial effects of ACE inhibitor treatment on glomerulosclerosis associated with diabetic nephropathies.