RESUMEN
The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension.
Asunto(s)
Aterosclerosis/metabolismo , Enfermedades Autoinmunes/metabolismo , Sistema Cardiovascular/metabolismo , Hipertensión Esencial/metabolismo , Proteínas de Choque Térmico/metabolismo , Animales , Aterosclerosis/inmunología , Aterosclerosis/fisiopatología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/fisiopatología , Autoinmunidad , Sistema Cardiovascular/inmunología , Sistema Cardiovascular/fisiopatología , Hipertensión Esencial/inmunología , Hipertensión Esencial/fisiopatología , Humanos , Transducción de SeñalRESUMEN
Considerable insight has been gained into the etiopathogenesis of poststreptococcal glomerulonephritis since the landmark theoretical construct of Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever. Over the years, molecular mimicry between streptococcal products and renal components, autoimmune reactivity and several streptococcal antigens have been extensively studied. Recent investigations assign a critical role to both in situ formation and deposition of circulating immune complexes that would trigger a variety of effector mechanisms. Glomerular plasmin-binding activity of streptococcal glyceraldehyde-3-phosphate-dehydrogenase may play a role in nephritogenicity and streptococcal pyrogenic exotoxin B and its zymogen precursor may be the long-sought nephritogenic antigen.
Asunto(s)
Glomerulonefritis/etiología , Glomerulonefritis/microbiología , Infecciones Estreptocócicas/inmunología , Animales , Proteínas Bacterianas/inmunología , Exotoxinas/inmunología , Fibrinolisina/metabolismo , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Gliceraldehído-3-Fosfato Deshidrogenasas/inmunología , Humanos , Glomérulos Renales/metabolismo , Modelos Inmunológicos , Imitación Molecular , Escarlatina/inmunología , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/patología , Streptococcus pyogenes/química , Streptococcus pyogenes/patogenicidadRESUMEN
Gómez-Garre et al. report increased expression of connective tissue growth factor and transforming growth factor-beta and worsening of remodeling in subcutaneous arterioles of patients with essential hypertension during amlodipine treatment. Losartan improves remodeling without changes in cytokine expression. The discordant effects of two well-accepted treatments for hypertension underline the need for further studies on therapy-induced changes in arteriolar remodeling.
Asunto(s)
Arteriolas/fisiopatología , Hipertensión/fisiopatología , Proteínas Inmediatas-Precoces/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Factor de Crecimiento Transformador beta/fisiología , Amlodipino/efectos adversos , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Factor de Crecimiento del Tejido Conjuntivo , Humanos , Hipertensión/tratamiento farmacológico , Losartán/uso terapéuticoRESUMEN
Bovine serum albumin (BSA) injected into the rabbits induces acute immune complex glomerulonephritis. Since albumin is filtered and reabsorbed in the tubules, we investigated whether tubulointerstitial cells participate in the pathogenesis of this experimental condition. For this purpose, we induced immune-complex nephritis in 45 rabbits with the injection of 125I-BSA and urinary BSA excretion, glomerular and tubulointerstitial BSA accumulation, lymphocyte infiltration, proliferative activity and MHC class II antigens were examined 2, 4-5 and 6-8 days after immunization. Proteinuria developed day 6-8. BSA was found in urine from day 2 (mean +/- SE; 1089 +/- 339 micro g/24 h) and peaked on day 4 after immunization (2249 +/- 1106). BSA content (cpm/g tissue) in tubulointerstitium (TI) and glomeruli were similar at day 2 (457 +/- 45 and 407 +/- 75, respectively), but afterward increased significantly in TI, reaching a peak level on day 5 (1026 +/- 406) while remained unchanged in glomeruli (388 +/- 95). At the same time, preceding the onset of proteinuria, maximal intensity of the lymphocyte infiltration, proliferative activity and MHC class II antigen expression in tubular cells, monocytes/macrophages and interstitial cells were observed. Our study shows that antigen is excreted in the urine and concentrated in TI in association with overexpression of MHC class II molecules and lymphocyte infiltration. These findings occur prior to the development of proteinuria and suggest that the tubulointerstitial cells play a critical role in the pathogenesis of this model.
Asunto(s)
Antígenos/análisis , Túbulos Renales/inmunología , Enfermedad del Suero/inmunología , Animales , Antígenos/orina , Antígenos de Histocompatibilidad Clase II/análisis , Antígenos de Histocompatibilidad Clase II/orina , Radioisótopos de Yodo , Glomérulos Renales/química , Glomérulos Renales/inmunología , Túbulos Renales/química , Linfocitos/inmunología , Proteinuria , Conejos , Albúmina Sérica Bovina/administración & dosificación , Albúmina Sérica Bovina/análisis , Factores de TiempoAsunto(s)
Fármacos Dermatológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Ácido Micofenólico/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Óxido Nítrico Sintasa/antagonistas & inhibidores , Enfermedades de la Piel/tratamiento farmacológico , Inmunología del TrasplanteAsunto(s)
Trasplante de Riñón/fisiología , Riñón/diagnóstico por imagen , Ultrasonografía Doppler , Humanos , Enfermedades Renales/diagnóstico por imagen , Trasplante de Riñón/patología , Necrosis Tubular Aguda/diagnóstico por imagen , Complicaciones Posoperatorias/diagnóstico por imagen , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.
Asunto(s)
Hipertensión/prevención & control , Inmunosupresores/farmacología , Ácido Micofenólico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/patología , Hipertensión/inducido químicamente , Riñón/metabolismo , Riñón/patología , Linfocitos/inmunología , Macrófagos/inmunología , Masculino , Ácido Micofenólico/análogos & derivados , NG-Nitroarginina Metil Éster , Nefritis Intersticial/inducido químicamente , Nefritis Intersticial/inmunología , Nefritis Intersticial/patología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/análisisRESUMEN
BACKGROUND: Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion. METHODS: Sprague-Dawley rats received Ang II for two weeks using subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks. RESULTS: MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 +/- 30 Ang II-positive cells/mm(2) at 8 weeks) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang II. The expression of Ang II receptors in the kidney was unmodified. CONCLUSIONS: SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN.
Asunto(s)
Angiotensina II/farmacología , Antiinflamatorios no Esteroideos/farmacología , Hipertensión Renal/tratamiento farmacológico , Ácido Micofenólico/farmacología , Vasoconstrictores/farmacología , Angiotensina II/análisis , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal , División Celular/fisiología , Creatinina/sangre , Modelos Animales de Enfermedad , Fibronectinas/análisis , Hipertensión Renal/inducido químicamente , Hipertensión Renal/prevención & control , Riñón/química , Riñón/inmunología , Riñón/patología , Leucocitos Mononucleares/inmunología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/orina , Ácido Micofenólico/análogos & derivados , Osteopontina , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/análisis , Sialoglicoproteínas/análisis , Superóxidos/metabolismo , Vasoconstrictores/análisisRESUMEN
Renal infiltration with macrophages and monocytes is a well-recognized feature of not only immune, but also nonimmune kidney disease. This review focuses on the investigations that have shown accumulation of immunocompetent cells in experimental models of acute and chronic ischemia, protein overload, hypercholesterolemia, renal ablation, obstructive uropathy, polycystic kidney disease, diabetes, aging, murine hypertension, and nephrotoxicity. We examine the mechanisms of infiltration of immunocompetent cells and their participation in the self-perpetuating cycle of activation of the angiotensin system, generation of reactive oxygen species, and further recruitment of monocytes and lymphocytes. We also discuss the possibility of antigen-dependent and antigen-independent mechanisms of immune cell activation in these animal models. Finally, we review the recent studies in which suppression of cellular immunity with mycophenolate mofetil has proven beneficial in attenuating or preventing the progression of renal functional and histologic damage in experimental conditions of nonimmune nature.
Asunto(s)
Enfermedades Renales/inmunología , Enfermedades Renales/patología , Animales , Antígenos/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunocompetencia , Inmunosupresores/farmacología , Enfermedades Renales/tratamiento farmacológico , Activación de Linfocitos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/patología , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Modelos Biológicos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacologíaRESUMEN
Intravenous iron (Fe) and recombinant human erythropoietin (rHuEPO) are routine treatments in the management of anemia in patients with chronic renal failure. We investigated the oxidative stress acutely induced by these therapies and whether pretreatment with oral melatonin (MEL) would have a beneficial effect. Nine patients (four women) were studied within 1 month of entering a chronic hemodialysis program in the interdialytic period. Plasma malondialdehyde (MDA), red blood cell glutathione (GSH), and catalase (CAT) activity were measured in blood samples obtained before (baseline) and 1, 3, and 24 hours after the administration of Fe (100 mg of Fe saccharate intravenously over 1 hour) or rHuEPO (4,000 U intravenously). One hour before these treatments, patients were administered a single oral dose of MEL (0.3 mg/kg) or placebo. Each patient was studied on four occasions, corresponding to studies performed using either placebo or MEL in association with intravenous Fe and rHuEPO administration. Baseline data showed increased oxidative stress in patients with end-stage renal failure. Increments in oxidative stress induced by Fe were more pronounced at the end of the administration: MDA, baseline, 0.74 +/- 0.09 nmol/mL; 1 hour, 1.50 +/- 0.28 nmol/mL (P: < 0.001); GSH, baseline, 2.51 +/- 0.34 nmol/mg of hemoglobin (Hb); 1 hour, 1.66 +/- 0.01 nmol/mg Hb (P: < 0.001); and CAT activity, baseline, 27.0 +/- 5.7 kappa/mg Hb; 1 hour, 23.3 +/- 4.2 kappa/mg Hb (P: < 0.001). rHuEPO-induced increments in oxidative stress were more pronounced (P: < 0.001) at 3 hours (MDA, 1.24 +/- 0.34 nmol/mL; GSH, 1.52 +/- 0.23 nmol/mg Hb; CAT activity, 18.0 +/- 3.1 kappa/mg Hb). MEL administration prevented the changes induced by Fe and rHuEPO and had no adverse side effects. These studies show that intravenous Fe and rHuEPO in doses commonly used to treat anemia in chronic hemodialysis patients acutely generate significant oxidative stress. Oral MEL prevents such oxidative stress and may be of clinical use.
Asunto(s)
Anemia/tratamiento farmacológico , Eritropoyetina/efectos adversos , Hierro/efectos adversos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Melatonina/farmacología , Estrés Oxidativo/efectos de los fármacos , Diálisis Renal , Adulto , Anemia/sangre , Anemia/etiología , Catalasa/sangre , Método Doble Ciego , Eritrocitos/química , Eritrocitos/enzimología , Eritropoyetina/administración & dosificación , Eritropoyetina/uso terapéutico , Femenino , Glutatión/sangre , Humanos , Infusiones Intravenosas , Hierro/administración & dosificación , Hierro/uso terapéutico , Fallo Renal Crónico/sangre , Masculino , Malondialdehído/sangre , Melatonina/administración & dosificación , Melatonina/uso terapéutico , Placebos , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
BACKGROUND: To develop a test that would disclose subclinical impairment in renal function, we studied the increment in tubular secretion of creatinine (TS(Cr)) induced by intravenous creatinine administration. METHODS: Studies were done in 14 normal individuals, 7 kidney donors (KDs), and 11 transplant recipients (Tx), all of whom had normal creatinine levels (P(Cr) <133 micromol/L). Creatinine infusion studies determined that maximal stimulation of TS(Cr) resulted from P(Cr) levels of 500 to 700 micromol/L. Therefore, in the tubular stress test, clearances, urinary excretion of creatinine (U(Cr)V) and TS(Cr) were determined before and after (15 to 105 min) a single bolus injection of 88.4 mmol/kg body wt, which resulted in the target P(Cr) levels. RESULTS: Baseline determinations of P(Cr), U(Cr)V, and TS(Cr) were not significantly different in the study groups. Stimulated U(Cr)V (nmol/kg/min) was higher in normals (426 +/- 82) than in KDs (338 +/- 72, P < 0.05) and Tx patients (311 +/- 66, P < 0.01). Similarly, TS(Cr) (nmol/kg/min) was higher (P < 0.001) in normals (180 +/- 60) than in KDs (155 +/- 54) and Tx patients (86 +/- 35). Furthermore, the transplanted kidney responded worse than the solitary normal kidney (P < 0.05), despite having similar levels of glomerular filtration rate (GFR). The tubular stress test increased TS(Cr) 11.3 +/- 6.2 times in normals, 4.3 +/- 1.2 times in KDs (P < 0.01), and 2.5 times in Tx (P < 0.001). CONCLUSIONS: Impaired tubular secretory response to a creatinine load is a more sensitive index of reduced functioning renal mass than levels of P(Cr) and GFR. The tubular stress test may be useful in following the natural history of kidney disease and the results of therapeutic interventions.
Asunto(s)
Creatinina/farmacocinética , Túbulos Renales/metabolismo , Adulto , Creatinina/administración & dosificación , Creatinina/sangre , Creatinina/orina , Tasa de Filtración Glomerular , Humanos , Inyecciones Intravenosas , Pruebas de Función Renal , Trasplante de Riñón , Valores de Referencia , Donantes de TejidosRESUMEN
We evaluated the effect of melatonin (Mel), a potent scavenger of reactive oxygen species, in the course of HgCl(2)-induced acute renal failure. Rats received by gastric gavage 1 mg/kg of Mel (n = 21) or vehicle (n = 21), 30 min before the subcutaneous injection of HgCl(2) (2.5 mg/kg). Rats were killed at 24, 48, and 72 h, and plasma creatinine (S(cr)), renal histology, proliferative activity, apoptosis, and superoxide-producing cells were studied. We also determined the renal content of malondialdehyde (MDA) and glutathione (GSH) and the activities of glutathione peroxidase and catalase. Mel pretreatment (Mel plasma levels of 3.40 +/- 3.15 microgram/ml at the time of HgCl(2) injection) prevented the increment in S(cr) and reduced tubular necrosis from 41.0 +/- 10.5 to 4.2 +/- 5.1% of proximal tubules (P < 0.01). Apoptosis and postnecrotic proliferative activity were twice more intense in the group untreated with Mel. Increment in renal content of MDA and decrease in GSH resulting from HgCl(2) toxicity were prevented by Mel. Mel also induced an important reduction in superoxide-positive cells. In contrast to the beneficial effects of pretreatment with Mel, the administration of Mel in conjunction with HgCl(2) had no effect on the oxidative damage and did not prevent nephrotoxicity. We conclude that the beneficial effects of pharmacological doses of Mel are due to its antioxidant properties.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Melatonina/farmacología , Estrés Oxidativo/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Animales , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Creatinina/sangre , Glutatión/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Melatonina/metabolismo , Cloruro de Mercurio , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-Dawley , Superóxidos/metabolismoRESUMEN
Cytomegalovirus (CMV) infections frequently develop in renal transplant patients. The transplanted kidney may be not only the source of infection but also the target for it. We report a case of primary CMV infection in a seronegative patient who received a graft from a seropositive cadaveric donor. The onset of CMV was clinically apparent on post-transplant day 22. Interestingly, soon after transplantation, the patient developed a long-lasting graft dysfunction episode for which diffuse endothelial-cell swelling was the most relevant finding at biopsy. On sonography, renal graft vascular impedance deteriorated and improved repeatedly during the follow-up period. We postulate that the patient had CMV-induced immunogenic-mediated endothelial-cell injury.
Asunto(s)
Infecciones por Citomegalovirus/diagnóstico por imagen , Infecciones por Citomegalovirus/patología , Trasplante de Riñón/efectos adversos , Ultrasonografía Doppler , Adulto , Biopsia con Aguja , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/etiología , Estudios de Seguimiento , Ganciclovir/administración & dosificación , Supervivencia de Injerto , Humanos , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Masculino , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Resultado del TratamientoRESUMEN
Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the development of atherosclerosis. We tested the effect of mycophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n=10 each) of New Zealand White (NZW) rabbits were fed a 1% cholesterol diet for 12 weeks. One group received MMF (CHOL+MMF group) by gastric gavage (30 mg/kg daily) and the other group (CHOL) received the same volume of saline by the same route. There were no differences in the serum cholesterol (mean values > or =30 mmol/l in both groups after 2 weeks) or in the triglyceride, blood sugar, total protein, and albumin serum levels and weight gain in both groups of animals. The cholesterol-fed untreated rabbits had atherosclerotic plaques covering 43.9.1+/-SD 16.40% of their thoracic aorta and 41.9+/-22. 59% of their abdominal aorta, while the MMF treated group had 18. 5+/-7.17% and 17.7+/-9.71%, respectively (P<0.01). The cholesterol content of the aorta (mg/g) in the cholesterol-fed untreated group was 4.61+/-SD 1.21 in the thoracic aorta and 4.54+/-2.07 in the abdominal aorta, whereas the MMF treated group had and 2.83+/-0.84 and 2.77+/-1.44, respectively (P<0.01). Infiltrating macrophages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta were 58.4+/-SD26.16 in the CHOL group and 8.5+/-5.51 in the CHOL+MMF group: (P<0.001). CD18 positive cells/100 nuclei were 27.4+/-17.6 in the CHOL group and 5.3+/-3.82 in the CHOL+MMF group (P<0.01), and the intima/media ratio was 0.66+/-0.11 in the CHOL group and 0. 30+/-0.09 in the MMF treated rabbits (P<0.001). MMF also reduced proliferating smooth muscle cells (HHF35 positive) infiltrating between the macrophages. These results indicate that MMF ameliorates importantly the atherogenic potential of a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinely in various clinical conditions with relatively minor side effects, consideration may be given to its use as adjuvant therapy in atherosclerotic cardiovascular disease.
Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/patología , Inhibidores Enzimáticos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Ácido Micofenólico/análogos & derivados , Análisis de Varianza , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/patología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Colesterol/análisis , Colesterol/sangre , Dieta Aterogénica , Modelos Animales de Enfermedad , Inmunohistoquímica , Masculino , Ácido Micofenólico/farmacología , Conejos , Valores de Referencia , Estadísticas no ParamétricasRESUMEN
Treatment with cyclosporin A (CsA) improves proteinuria and reduces renal cellular infiltration in chronic serum sickness (CSS). We examined if these effects were associated with a reduced renal expression of CD54 and its ligands, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and MHC class II molecules. We studied two groups of rats in which CSS was induced by daily injections of ovalbumin (OVA): a group treated with CsA (OVA.CsA group, n = 11) and a group that received no treatment (OVA.CSS group, n = 11). An additional group of five rats (control group) received only phosphate buffer. Immunostaining techniques were used to follow CSS and to study the expression of CD54, CD18, CD11b/c, IFN-gamma, TNF-alpha and MHC class molecules. Proteinuria (mg/24 h) was reduced from 248.2 +/- 73.1 (OVA.CCS group) to 14.5 +/- 13.1 with CsA treatment (P < 0.0001). The renal expression of CD54 and its ligands (CD18 and CD11b/c) was reduced by 50% to 75%. Correspondingly, there was a 60% to 85% reduction in the number of infiltrating leucocytes. The number of cells expressing TNF-alpha, IFN-gamma and MHC II molecules was also reduced. CsA reduces expression of CD54 and its ligands. This effect is associated with a reduction of cellular infiltration, IFN-gamma, TNF-alpha-producing cells and with MHC II expression in the kidney. These findings suggest that expression of adhesion molecules plays a critical role in CSS and underline the importance of cellular immunity in this experimental model.
Asunto(s)
Ciclosporina/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Inmunosupresores/uso terapéutico , Molécula 1 de Adhesión Intercelular/biosíntesis , Riñón/metabolismo , Nefritis/tratamiento farmacológico , Enfermedad del Suero/tratamiento farmacológico , Animales , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Quimiotaxis de Leucocito , Enfermedad Crónica , Creatinina/sangre , Ciclosporina/farmacología , Modelos Animales de Enfermedad , Antígenos de Histocompatibilidad/biosíntesis , Antígenos de Histocompatibilidad/genética , Enfermedades del Complejo Inmune/tratamiento farmacológico , Enfermedades del Complejo Inmune/etiología , Inmunización , Inmunosupresores/farmacología , Molécula 1 de Adhesión Intercelular/genética , Interferón gamma/biosíntesis , Interferón gamma/genética , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Masculino , Microscopía Fluorescente , Nefritis/etiología , Nefritis/inmunología , Ovalbúmina/inmunología , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Ratas , Ratas Sprague-Dawley , Enfermedad del Suero/inmunología , Enfermedad del Suero/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The usefulness of pulsatility index determinations for the diagnosis of obstructive collecting system dilatation was investigated in 10 renal transplant patients whose grafts developed urinary obstruction from different causes. For this purpose we compared pulsatility index values obtained (1) before the ultrasonographic detection of obstruction or baseline study, (2) 1 day before surgical repair, and (3) within 2 weeks after surgery. In 7 of 10 obstructed grafts, the pulsatility index values were increased only mildly to moderately preoperatively. In the remaining three grafts, a mild decrease in pulsatility index was observed in spite of severe collecting system dilatation. Changes in pulsatility index were not statistically significant. Impedance measurements appeared not to be useful for diagnosing obstructive collecting system dilatation.