RESUMEN
Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB x NZW)F(1) background, disruption of estrogen receptor-alpha (ER alpha or Esr1) attenuated glomerulonephritis and increased survival. ER alpha deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ER alpha promotes loss of immunologic tolerance. Furthermore, ER alpha deficiency in (NZB x NZW)F(1) females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ER alpha may promote lupus, at least in part, by inducing interferon-gamma, an estrogen-regulated cytokine that impacts this disease. ER alpha deficiency in (NZB x NZW)F(1) males increased survival and reduced anti-dsDNA antibodies, suggesting that ER alpha also modulates lupus in males. These studies demonstrate that ER alpha, rather than ER beta, plays a major role in regulating autoimmunity in (NZB x NZW)F(1) mice. Furthermore, our results suggest for the first time that ER alpha promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ER alpha, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.
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Receptor alfa de Estrógeno/deficiencia , Receptor alfa de Estrógeno/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Animales , Receptor alfa de Estrógeno/fisiología , Femenino , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Endogamia , Lupus Eritematoso Sistémico/prevención & control , Masculino , Ratones , Ratones Endogámicos NZB , Ratones NoqueadosRESUMEN
AIMS/HYPOTHESIS: Type 2 diabetes often results in diabetic nephropathy, which is preceded by an elevated glomerular filtration rate (GFR). This study was designed to develop a mouse model of Type 2 diabetes and to elucidate the glomerular events in the early stages of diabetic nephropathy. METHODS: Four-week-old mice were fed a normal or high-fat (42% of total calories from fat) diet, and body weight, blood glucose, insulin, leptin, lipids and GFR were monitored from 9 to 21 weeks or longer after the feeding programme. Mesangial cell dedifferentiation was accessed by alpha-smooth muscle actin staining. Glomerular hypertrophy was determined using image analysis with haematoxylin-eosin staining. Matrix deposition was determined by type IV collagen staining. RESULTS: After 9 weeks, mice fed a high-fat diet weighed more than mice fed a normal diet (30.5+/-1.2 vs 22.3+/-0.5 g, p<0.05), and mice fed a high-fat diet were hyperinsulinaemic (283.9+/-69.7 vs 102.9+/-36.4 pmol/l, p<0.05), hyperglycaemic (8.0+/-0.6 vs 6.5+/-0.2 mmol/l, p<0.05) and their leptin levels were increased six-fold (1.48+/-0.45 vs 0.25+/-0.03 ng/ml, p<0.05). After 13 weeks, mice fed a high-fat diet showed hyperfiltration (GFR; 440+/-60 vs 210+/-10 microl/min, p<0.05). During the early stages of diabetic nephropathy, mesangial cell dedifferentiation was evident, shown by increased expression of alpha-smooth muscle actin in the glomeruli. After 9 weeks, mice fed a high-fat diet already demonstrated increased type IV collagen deposition. After 13 weeks, they developed enlarged glomerular tufts compared with those of their age-matched controls. CONCLUSIONS/INTERPRETATION: The results of this study suggest that collagen IV deposition precedes the hyperfiltration and enlargement of glomeruli in early-stage diabetic nephropathy. Dedifferentiation of mesangial cells may be associated with collagen IV deposition.
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Diabetes Mellitus Tipo 2/patología , Grasas de la Dieta , Glomérulos Renales/patología , Animales , Glucemia/metabolismo , Peso Corporal , Diferenciación Celular , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Insulina/sangre , Glomérulos Renales/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Aumento de PesoRESUMEN
Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4- or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2- to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four- to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.
Asunto(s)
Infecciones por Coxsackievirus/complicaciones , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/prevención & control , Enterovirus Humano B/patogenicidad , Animales , Apoptosis , Autoanticuerpos/metabolismo , Autoantígenos , Infecciones por Coxsackievirus/patología , Infecciones por Coxsackievirus/virología , Diabetes Mellitus Tipo 1/patología , Enterovirus Humano B/clasificación , Enterovirus Humano B/genética , Enterovirus Humano B/fisiología , Femenino , Humanos , Inmunoglobulina G/metabolismo , Hibridación in Situ , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/patología , Islotes Pancreáticos/virología , Ratones , Ratones Endogámicos NOD , Modelos Biológicos , Especificidad de la Especie , Replicación ViralRESUMEN
Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in many progressive kidney diseases. The present study examines this growth factor during the pubertal and early adult periods. Mixed-sex Munich-Wistar rat kidneys were obtained on selected days of life from birth through 6 months of age. A survey of the TGF-beta 1 system was performed, and then a second experiment focused on cortex and medulla from both sexes at 6 weeks and 16 weeks of age. Reverse transcription polymerase chain reaction for TGF-beta 1 and TGF-beta inducible gene H3 (beta IG-H3) was performed. Active and total levels of protein for TGF-beta 1 were isolated from tissue. Active levels of TGF-beta 1 were somewhat lower in older than in younger animals, without sex differences. beta IG-H3 levels were similar. At 16 weeks females had levels of total growth factor approximately threefold greater than males, while adult males appeared to activate the growth factor much more efficiently. These findings suggest that activation of TGF-beta 1 becomes more efficient following puberty in the male rat, while females appear to have reduced activation efficiency compensated by increased total growth factor. These differences may help explain the deterioration at puberty and sexual dimorphism noted with some progressive nephropathies.
Asunto(s)
Riñón/metabolismo , Caracteres Sexuales , Maduración Sexual/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Femenino , Inmunohistoquímica , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Distribución Tisular , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1RESUMEN
Prepubertal years of diabetes mellitus are relatively protected from clinical manifestations of nephropathy. Transforming growth factor-beta1 (TGF-beta1) is a major mediator of diabetic kidney disease. Its renal expression, translation, and activation change with sexual maturation in the normal rat. The role of TGF-beta1 in postpubertal susceptibility to diabetic renal hypertrophy was addressed in the present study. Male Sprague- Dawley rats were given streptozocin at 4 weeks of age (weanling) or 14 weeks of age (mature) and treated with insulin to maintain blood glucose levels between 300 and 500 mg/dl. Nondiabetic controls received saline. After 6 weeks with ad libitum food and water, kidneys were snap-frozen for measurement of TGF-beta1 protein and mRNA. As in previous studies, diabetic renal hypertrophy was blunted in weanling animals compared with mature rats. Message for TGF-beta1 was not significantly increased in weanling animals [102 (9)% [mean (SEM)] in nondiabetic controls versus 117 (10)% in diabetic rats; P=0.91], while it was significantly increased in mature diabetic animals [100 (7)% vs. 146 (11)%; P=0.01]. Immunohistochemistry revealed focal increases in glomerular staining in mature but not weanling diabetic rats. Differences in the control of the renal TGF-beta system may explain the permissive role of puberty in the manifestations of diabetic kidney disease.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Riñón/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Envejecimiento/metabolismo , Animales , Inmunohistoquímica , Glomérulos Renales/metabolismo , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1RESUMEN
Transforming growth factor beta (TGF-beta) is a major promoter of diabetic nephropathy. While TGF-beta1 is the most abundant renal isoform, types 2 and 3 are present as well and have identical in vitro effects. Whole kidney extracts were studied 2 weeks after induction of streptozocin diabetes and in control rats. Mean glomerular area was 25% greater in the diabetic animals. TGF-beta1 showed a 2-fold increase in message with a 3-fold increase in protein. TGF-beta2 mRNA increased approximately 6% while its protein doubled. TGF-beta-message increased by 25%, producing a 35% increase in its protein. TGF-beta-inducible gene H3 mRNA was increased 35% in the diabetic animals, consistent with increased activity of this growth factor. All isoforms of TGF-beta are increased in the diabetic rat kidney. Future studies need to address the specific role that each isoform plays in diabetic nephropathy as well as the impact of therapies on each isoform.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Riñón/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Secuencia de Bases , Cartilla de ADN , Diabetes Mellitus Experimental/patología , Riñón/patología , Cinética , Masculino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1 , Factor de Crecimiento Transformador beta2 , Factor de Crecimiento Transformador beta3RESUMEN
Studies of early nephropathy in streptozocin (STZ)-treated rats are complicated by the nephrotoxicity of this agent. Inhibitors of the diabetogenic actions of STZ have been described, but their effects on the kidney have not been assessed. This study examined the effects of one agent, 5-thio-D-glucose (5TG) on renal hypertrophy and transforming growth factor beta1 (TGF-beta1). Forty male Sprague Dawley rats were divided into four groups: saline controls (SC), 5TG alone, 5TG + STZ, and STZ. After 2 weeks of observation, urine, plasma, and kidneys were studied. Nine of 10 STZ rats were diabetic at the time of euthanasia, as were 5 of 10 5TG + STZ animals. Both tissue levels of messenger RNA and protein for active and total TGF-beta1 were elevated in STZ and 5TG-STZ animals compared with SC. 5TG also elevated mRNA and produced protein levels intermediate to the other groups. 5TG plus STZ is an unacceptable control for nephropathy studies in STZ diabetes, both because of lack of efficacy at the dose studied and the induction of TGF-beta1 by 5TG. 5TG may yet prove of value in studying control of renal TGF-beta1 expression and excretion.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Diabetes Mellitus Experimental/prevención & control , Glucosa/análogos & derivados , Riñón/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Glucosa/farmacología , Inmunohistoquímica , Riñón/efectos de los fármacos , Riñón/patología , Masculino , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
The group B coxsackieviruses (CVB) induce experimental pancreatitis and myocarditis in mice and are established agents of human myocarditis, especially in children. We tested the hypothesis that the development of CVB-induced myocarditis is linked to CVB-induced pancreatitis by studying the replication of different CVB strains in mice. Eight of nine genotypically different type 3 CVB (CVB3) strains induced acute pancreatitis in mice; of these, three viruses also induced acute myocarditis. One CVB3 strain was avirulent for both organs. Myocarditis was not observed in the absence of pancreatitis. The results obtained by inoculation of mice with strains of other CVB serotypes were consistent with these data. Infectious virus titers were measured in serum, pancreas, and heart as a function of time after inoculation of mice with three CVB3 strains. Each strain was representative of one of the three viral virulence phenotypes: avirulent, pancreovirulent only, and cardiovirulent. All strains replicated well and persisted in the pancreas through 8 days post-inoculation, but the cardiovirulent CVB3 strain tended to replicate to higher titer earlier and persist longer in sera, pancreatic, and cardiac tissues than the noncardiovirulent strains. Replication of the CVB3 strains were studied in two human pancreatic tumor lines and in primary human endothelial cell cultures derived from cardiac artery. Cardiovirulent strains, both individually and as a group, tended to replicate to titers as high as, or higher than, noncardiovirulent strains did in cell culture. The data are consistent with the possibility of an etiologic link between CVB-induced pancreatic and heart disease.
Asunto(s)
Infecciones por Coxsackievirus/virología , Enterovirus Humano B/patogenicidad , Miocarditis/virología , Pancreatitis/virología , Enfermedad Aguda , Adulto , Animales , Células Cultivadas , Niño , Preescolar , Infecciones por Coxsackievirus/complicaciones , Infecciones por Coxsackievirus/patología , Enterovirus Humano B/crecimiento & desarrollo , Enterovirus Humano B/aislamiento & purificación , Femenino , Células HeLa , Corazón/virología , Humanos , Recién Nacido , Masculino , Ratones , Ratones Endogámicos , Miocarditis/complicaciones , Miocarditis/patología , Miocardio/patología , Páncreas/patología , Páncreas/virología , Pancreatitis/complicaciones , Pancreatitis/patología , Fenotipo , Virulencia , Replicación ViralRESUMEN
Furosemide treatment produces glomerular hypertrophy and augments glomerular capillary hydraulic pressure in the normal rat. Similar processes have been implicated in the progression of glomerulosclerosis (GS). Whereas prior experiments with furosemide treatment of 6 to 8 weeks duration have produced no detrimental effects on renal function or structure, the effects of more prolonged treatment are unknown. Male Munich-Wistar rats were pair fed with or without furosemide, 40 mg/d, from the time of weaning through 10 months of age. At selected time points, 24-hour urine collections were obtained for total protein and volume determination. At the end of the study, light and electron microscopic morphometric studies were performed. Renal cortical hypertrophy and glomerular hypertrophy were sustained throughout the 9 months of treatment in the group receiving furosemide. The cortical interstitial area was increased in the furosemide group, but this did not appear to be the result of fibrosis. Proximal and distal tubule diameter were unaffected by treatment. No differences in GS or glomerular ultrastructure were shown. This study provides no evidence of detrimental glomerular effects of furosemide in normal animals. Further studies of furosemide treatment under conditions of preexisting renal pathological conditions are warranted to confirm the safety of this treatment in situations analogous to those seen in the clinical setting. Interstitial expansion also warrants further study in this setting.
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Furosemida/efectos adversos , Glomeruloesclerosis Focal y Segmentaria/patología , Glomérulos Renales/efectos de los fármacos , Animales , Hipertrofia , Corteza Renal/efectos de los fármacos , Corteza Renal/patología , Corteza Renal/ultraestructura , Glomérulos Renales/patología , Glomérulos Renales/ultraestructura , Túbulos Renales/patología , Masculino , Proteinuria/inducido químicamente , RatasRESUMEN
Angiotensin II (ANG II) is believed to promote progressive renal injury via augmented glomerular capillary hydraulic pressure (PGC). Acute volume reduction secondary to diuretic administration increases circulating ANG II and augments PGC, yet the hemodynamic effects of sustained diuretic administration are unknown. Therefore, glomerular micropuncture studies were performed in male Munich-Wistar rats after 6-8 wk of treatment with daily furosemide (F, 40 mg/day), furosemide plus the AT1 receptor antagonist, losartan (F + L, 5 mg/day), or no therapy (C, control). Renal weight was increased in F rats (1.23 +/- 0.7 g) vs. C (1.00 +/- 0.06 g) or F + L (0.97 +/- 0.01 g). In addition, PGC was elevated in F animals (52.1 +/- 1.5 mmHg) vs. C (43.7 +/- 1.5) or F + L-treated rats (41.3 +/- 1.7). F-treated rats were also characterized by a relative increase in efferent arteriolar resistance and filtration fraction. The latter was markedly attenuated in F + L-treated animals. Collectively, these findings are consistent with an ANG II-mediated alteration in intrarenal hemodynamics. In contrast to acute volume manipulations, however, chronic furosemide augmented renal growth, whereas losartan administration completely arrested this phenomenon. Further studies are warranted to determine whether the hemodynamic and growth adaptations elicited by chronic F administration induce or accelerate renal injury.
Asunto(s)
Capilares/fisiología , Furosemida/farmacología , Glomérulos Renales/irrigación sanguínea , Riñón/efectos de los fármacos , Losartán/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Capilares/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/anatomía & histología , Riñón/fisiología , Masculino , Nefronas/efectos de los fármacos , Nefronas/fisiología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Somatometric parameters, renal size, and systolic blood pressure (SBP) were studied in 406 patients referred to pediatric nephrology and urology clinics. These patients included 269 females (66%), 67 African Americans (17%), and 87 patients with essential hypertension (21%). Z scores for the study population were comparable to published standards for height, kidney length, and SBP. Weight and body mass index scores were significantly greater than predicted from the standards, especially in the subset of patients with essential hypertension. Age, height, weight, body mass index, kidney length, and SBP all correlated with one another; however, on multiple regression analysis of SBP with the other five independent variables, only weight proved to have a significant correlation. Furthermore, the relationship of kidney length with SBP was positive and hypertensive patients had greater kidney size than published standards. These data do not support reduced kidney size in the population with essential hypertension, nor is there support for a convincing correlation between kidney length and SBP in the general pediatric population. Body weight correlates best with blood pressure. These findings warrant further study in a less-select population. Prevention and treatment of obesity may thus be of prime importance in addressing hypertension in children.
Asunto(s)
Presión Sanguínea/fisiología , Peso Corporal/fisiología , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Riñón/patología , Riñón/fisiopatología , Adolescente , Índice de Masa Corporal , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Nefronas/anatomía & histología , Nefronas/fisiología , Análisis de RegresiónRESUMEN
To define the earliest renal morphological changes in patients with type I diabetes, we studied renal function and morphometric analysis of renal biopsies in 59 patients with diabetes for 5-12 years and normal blood pressure, normal creatinine clearance (CCr), and negative dipstick urinary protein. Arteriolar hyalinization and intimal fibrous thickening were noted in 43%. Glomerular basement membrane thickness and fractional mesangial volume were increased in 51% and 56%, respectively. The pre-pubertal and post-pubertal years of diabetes were associated with similar degrees of renal structural changes, but during the pre-pubertal years normal urinary albumin excretion (UAE) was seen. Principal factor analysis of morphometric structural parameters yielded four clusters of variables: "glomerular size" correlated with patient age, CCr, and UAE; "peripheral capillary decrease" correlated with glycosylated hemoglobin, diastolic blood pressure, glomerular filtration rate, and UAE; "mesangial increase" correlated with UAE; and "interstitial scarring" correlated with diastolic blood pressure. This study provides unique documentation of renal structural abnormalities which precede clinically evident renal functional abnormalities and documents that these early structural abnormalities are present in the pre-pubertal years of diabetes as well as postpuberty, and are associated with each other in constellations that correspond to postulated mechanisms in diabetic nephropathy.
Asunto(s)
Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Riñón/patología , Riñón/fisiopatología , Adolescente , Adulto , Niño , Análisis Factorial , Femenino , Tasa de Filtración Glomerular , Humanos , Pruebas de Función Renal , Masculino , Valores de ReferenciaRESUMEN
Prepubertal years of insulin-dependent diabetes mellitus are protected from the nephropathic effects of this disease, yet this effect of immaturity has not been investigated in an animal model. Male Munich-Wistar rats were made diabetic with streptozocin at two ages: weanling (approximately 4 wk) and pubescent (approximately 10 wk). After 5 wk of untreated diabetes, weanling diabetic animals showed relatively greater growth of the medulla, whereas relative proportions of these areas were constant in the older animals. Glomerular volume increased by approximately 35% in older diabetic animals, but no glomerular enlargement was demonstrated in weanling rats with diabetes. Glomerular ultrastructure was not significantly altered during the short course of this study. The renal structural response to diabetes is age-dependent in the rat, with prepubertal animals protected from glomerular hypertrophy. Longer studies are needed to see if these differences will eventually parallel those demonstrated in patients with onset of diabetes before and after puberty. This model may ultimately prove to be valuable in determining the mechanism via which prepubertal kidneys are protected from the nephropathic effects of insulin-dependent diabetes mellitus.
Asunto(s)
Envejecimiento/fisiología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Riñón/patología , Edad de Inicio , Animales , Diabetes Mellitus Tipo 1/patología , Mesangio Glomerular/patología , Corteza Renal/patología , Glomérulos Renales/patología , Médula Renal/patología , Masculino , Tamaño de los Órganos , Ratas , Ratas Wistar , Maduración SexualRESUMEN
BACKGROUND: Mean glomerular volume (VG) determined by Cavalieri, maximal profile area (MPA), and Weibel-Gomez methods correlated in paraffin-embedded needle biopsies; the Disector method did not correlate, probably because of sampling limitations. The relationship of these methods in other types of specimens has not been established. EXPERIMENTAL DESIGN: Sections of whole kidneys from 19 rats, 10 treated with furosemide to increase VG, were immersion-fixed, embedded in glycol methacrylate, serially sectioned at 5 microns through 150 microns of tissue, and stained with Jones' silver stain. VG was determined by the Cavalieri, MPA, Disector, and Weibel-Gomez methods with three samples from each animal to assess the correlation, agreement, and repeatability of each of these methods. Methods were considered to correlate if p < 0.01 on linear regression analysis and to agree if the line of identity (x = y) fell within the 95% confidence interval for the slope of the regression curve. Repeatability was assessed with the coefficient of variation for each technique. RESULTS: Other methods correlated with the Cavalieri method (MPA r = 0.86, Disector r = 0.66, Weibel-Gomez r = 0.87), although none of these methods agreed with Cavalieri VG. These results were similar when treated animals, untreated animals, and all animals were analyzed. Cavalieri and MPA methods showed 7% coefficient of variation with repeated samples; the Disector method showed higher variation (12%), and Weibel-Gomez showed significantly higher variation when compared with the other methods (25%). CONCLUSIONS: MPA, Weibel-Gomez, and Disector methods all provide estimates of VG that correlate with Cavalieri VG; however, none gives the same value. Reasons for these discrepancies may include assumptions regarding glomerular shape and size distribution inherent in the various methods and the experimental conditions. Tissue availability will often dictate VG method, and consistency of method within an experiment is critical.
Asunto(s)
Glomérulos Renales/patología , Nefrectomía , Animales , Estudios de Evaluación como Asunto , Masculino , Patología/métodos , Ratas , Ratas EndogámicasRESUMEN
Diuretics are commonly used to treat a variety of conditions, including progressive nephropathies, cardiovascular, and pulmonary diseases. Such treatment stimulates the production of angiotensin II, an important mediator of renal growth which may accelerate progressive glomerulosclerosis. To further study the effects of diuretic treatment on normal renal growth and development, weanling male Munich-Wistar rats received no drug, enalapril, furosemide, or both drugs for 6 wk; morphometric studies were then performed using standard light and electron microscopic techniques. Plasma renin activity was elevated by furosemide treatment. Cortical tubular growth was stimulated in rats receiving furosemide or both drugs; enalapril did not affect cortical tubular growth when compared with untreated animals. Glomerular volume was increased in furosemide-treated animals, primarily due to an increase in the proportion of mesangial cells, whereas enalapril decreased glomerular volume. Furosemide also increased the filtration surface area per glomerulus whereas enalapril decreased it. Concurrent enalapril treatment blocked the furosemide-induced changes in filtration surface area as well as attenuating overall glomerular and mesangial growth. Glomerular changes correlated with plasma renin activity. Furosemide stimulated glomerular growth, especially of mesangial cells, probably via stimulation of AngII production. Given the relationship of mesangial cell growth and progressive renal disease, diuretic therapy could thus accelerate glomerulosclerosis. Cortical tubular growth also increased with furosemide; however, enalapril had no effect, so factors besides angiotensin II appeared to modulate tubulointerstitial growth in these animals.
Asunto(s)
Angiotensina II/fisiología , Enalapril/toxicidad , Furosemida/toxicidad , Riñón/efectos de los fármacos , Renina/sangre , Análisis de Varianza , Angiotensina II/biosíntesis , Animales , Evaluación Preclínica de Medicamentos , Riñón/crecimiento & desarrollo , Masculino , Ratas , Ratas Wistar , Análisis de RegresiónRESUMEN
Renal morphometric analysis was performed in 15 (13 male) Alport syndrome patients ages 4 to 26 years, along with 10 controls ages 3 to 26 years, to better understand the structural basis of renal dysfunction in Alport syndrome. The glomerular basement membrane (GBM) width class frequencies of controls were normally distributed; those of Alport syndrome patients were slightly skewed, especially toward thicker classes, although there was also an increase in the proportion of thinner classes. Mesangial volume fraction was not different between Alport syndrome patients (0.21 +/- 0.09) and controls (0.19 +/- 0.04). There was an inverse correlation between mesangial volume fraction and creatinine clearance in Alport syndrome patients (r = -0.72, P < 0.01); however, the creatinine clearances in Alport syndrome patients were far less than in insulin-dependent diabetic patients with similar mesangial volume fraction. Similarly, there was no significant difference in the surface density of the peripheral GBM (in square micrometers per cubic micrometer) in Alport syndrome patients (0.12 +/- 0.04) versus controls (0.13 +/- 0.02). The surface density of the peripheral GBM correlated with creatinine clearance in Alport syndrome patients (r = 0.71, P < 0.01). However, there was a greater reduction in creatinine clearance as related to declining the surface density of the peripheral GBM in Alport syndrome than in diabetic patients. The cortical interstitial volume fraction was highly inversely correlated with creatinine clearance in Alport syndrome patients (r = -0.85, P < 0.01). Global glomerular sclerosis was 0% in five and 5 to 61% in nine Alport syndrome patients and correlated inversely with creatinine clearance (r = -0.74, P < 0.01). However, the creatinine clearance was lower in Alport syndrome than in diabetic patients with similar cortical interstitial volume fraction and percent glomerular sclerosis. There was no significant difference in an index of glomerular number between Alport syndrome patients and controls. Thus, changes in mesangial volume fraction, cortical interstitial volume fraction, percent glomerular sclerosis, and surface density of the peripheral GBM in Alport syndrome patients only partially account for the reduction in creatinine clearance. It was speculated that decreased glomerular capillary wall hydraulic conductivity in Alport syndrome could explain many of these observations.
Asunto(s)
Nefritis Hereditaria/patología , Nefritis Hereditaria/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Creatinina/farmacocinética , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Femenino , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranoproliferativa/fisiopatología , Humanos , Riñón/patología , Riñón/fisiopatología , Glomérulos Renales/patología , Masculino , Valores de ReferenciaRESUMEN
Previous studies have demonstrated an association between renal cortical fatty acid composition and experimental models of renal injury. The present study was designed to extend these observations to the remnant kidney and to investigate the hypothesis that increased endogenous turnover of arachidonic acid metabolites results in the depletion of progenitor fatty acids. Remnant kidney cortex demonstrated a relative reduction of the essential fatty acids, linoleate and arachidonate (20 +/- 7.2% and 11 +/- 0.3%, respectively), nine weeks after subtotal nephrectomy. In addition, the monounsaturated fatty acid, oleate, was increased (48 +/- 10.6%) while its saturated progenitor, stearate, was decreased (13 +/- 4.3%). Serial evaluation of dienoic prostanoids revealed a significant increase in the renal excretion of TXB2 in rats with remnant kidneys (27 +/- 3.0, 29 +/- 1.1, and 34 +/- 3.3 ng/day vs. 21 +/- 0.8, 20 +/- 1.5, and 22 +/- 3.3 ng/day in control rats, at 3, 6, and 9 weeks, respectively). Moreover, TXB2 excretion inversely correlated with dienoic progenitor fatty acids [18:2(n-6), r2 = 0.76; 20:4(n-6), r2 = 0.79], suggesting that these events are biochemically coupled. Endogenous turnover of precursor fatty acids, confirmed by an increase in renal TXB2 excretion, preceded overt depletion of essential fatty acids by several weeks. Importantly, blockade of endogenous synthesis of TXA2 with the specific TXA2 synthase antagonist, U-63557A, restored the essential fatty acid composition to normal and ameliorated progressive glomerular destruction. Moreover, the ancillary fatty acid disturbances were attenuated by administration of U-63557A.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Benzofuranos/farmacología , Ácidos Grasos Esenciales/deficiencia , Riñón/efectos de los fármacos , Riñón/metabolismo , Animales , Dinoprostona/orina , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Ácidos Grasos Esenciales/metabolismo , Riñón/lesiones , Corteza Renal/metabolismo , Masculino , Modelos Biológicos , Nefrectomía , Ratas , Ratas Sprague-Dawley , Tromboxano A2/biosíntesis , Tromboxano B2/orina , Tromboxano-A Sintasa/antagonistas & inhibidores , Factores de TiempoRESUMEN
We have reviewed the clinical course of 30 pediatric bone marrow transplant (BMT) recipients requiring dialysis for acute renal failure early after BMT. Patients requiring dialysis were not significantly different from the general pediatric BMT population except for: (1) a greater proportion of neuroblastoma patients in the dialysis group, and (2) fewer autologous and more unrelated BMT donors in the dialysis group. Twenty-three patients (77%) died without recovering renal function 1-72 days (mean 12 days) after dialysis was begun. Sepsis was the most commonly cited cause of renal failure and death in these patients. Seven patients (23%) recovered sufficient renal function to stop dialysis; all long-term survivors were in this group. Factors at the onset of dialysis associated with persistent renal failure were weight gain of > or = 10% of baseline body weight, requirement of three or more drugs for blood pressure support and hyperbilirubinemia. Although acute renal failure requiring dialysis is an ominous development following BMT, recovery of renal function is possible with aggressive supportive care.
Asunto(s)
Lesión Renal Aguda/terapia , Trasplante de Médula Ósea/efectos adversos , Diálisis Renal , Lesión Renal Aguda/etiología , Adolescente , Niño , Preescolar , Femenino , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Lactante , MasculinoRESUMEN
Eighty-four patients with insulin-dependent diabetes mellitus had studies of renal function and quantitative renal morphometry including mesangial volume fraction (Vvmes/glom), index of arteriolar hyalinosis, percentage of globally sclerosed glomeruli (%GS), and interstitial volume fraction for total renal cortex (Vvint/T). There was significant correlation among these four parameters, and all four structural parameters correlated with glomerular filtration rate and the log of urinary albumin excretion. Stepwise multiple regression analysis showed that Vvmes/glom and Vvint/T were additive, suggesting that they are partially independent. Arteriolar hyalinosis and %GS did not improve the correlations further. We hypothesize that Vvmes/glom, Vvint/T, arteriolar hyalinosis, and %GS represent multiple but probably interrelated pathologic mechanisms leading to the functional disturbances of diabetic nephropathy. Longitudinal studies of patients with diabetes and studies of patients with diseases producing interstitial expansion in the absence of glomerular disease may help clarify the independent role of interstitial expansion in the kidney disease of diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 1/patología , Riñón/patología , Arteriolas/patología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Espacio Extracelular/fisiología , Femenino , Mesangio Glomerular/patología , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Riñón/irrigación sanguínea , Riñón/fisiopatología , Corteza Renal/patología , Masculino , Microscopía ElectrónicaRESUMEN
Acute administration of epidermal growth factor (EGF) has been shown to promote recovery from ischemic and nephrotoxic acute renal failure in vivo. The question of whether chronic subcutaneous administration of EGF (19.1 micrograms/day for 3 or 6 wk) could alter the course of chronic renal failure in rats subjected to 5/6 nephrectomy was studied. By week 6, there was no difference in renal function, as assessed by animal survival, BUN, urea and inulin clearances, proteinuria, renal morphometry, or renal size, between EGF- and vehicle-treated rats. This suggests that chronic renal insufficiency differs from acute tubular injury in its sensitivity to exogenous EGF. Unexpectedly, EGF significantly attenuated the rise in systolic blood pressure that occurred by the fourth week after 5/6 nephrectomy. The antihypertensive effect of EGF was still evident at week 5. Urinary flow rate, free water clearance, and excretion of total solutes, Na+, and K+, however, were not significantly altered by EGF at weeks 2, 4, 5, or 6, suggesting a mechanism other than increased natriuresis or diuresis for this antihypertensive effect.