RESUMEN

PURPOSE: To evaluate prospectively chronic gastrointestinal toxicity in patients with cervical cancer treated with conventional irradiation or with intensity-modulated irradiation (IMRT). PATIENTS AND METHODS: Between June 2005 and September 2013, 109 patients underwent external radiotherapy followed by brachytherapy for cervical cancer at the "Institut de Cancérologie de Lorraine". Each patient receiving IMRT was paired with a patient receiving conventional radiotherapy on the following criteria: concomitant chemotherapy, additional nodal dose, treatment of para-aortic lymph node area, age. The toxicity collection was prospective using the RTOG scale. The main objective was to compare the incidence of gastrointestinal toxicity chronic between the two groups. In a second time, the influence of dosimetric parameters on chronic GI toxicity was investigated. Comparisons of acute toxicity, chronic genitourinary toxicities, overall survival, disease-free survival were secondary objectives. RESULTS: Sixty-six patients were able to be matched. Overall survival at 36 months was 71% in the conventional radiotherapy group against 73% in the IMRT group (P=0.54). There was no significant difference between the two groups in terms of digestive chronic toxicity (P=0.17), nor in terms acute gastrointestinal toxicities (P=0.6445) and genitourinary (P=0.5724). IMRT spared significantly small bowel (P=0.0006) and rectum (P=0.0046) from 30Gy dose, and bladder from 45Gy (P<0.001). The incidence of genitourinary toxicity was significantly different between the two groups (P=0.03) in favor of conventional radiotherapy. CONCLUSION: Our study does not seem to show significant difference in the occurrence of chronic gastrointestinal toxicities between the two groups. Clinical efficacy seems comparable. Larger studies with longer follow-up period should be conducted.

Asunto(s)

Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/radioterapia , Enfermedades Gastrointestinales/etiología , Traumatismos por Radiación/etiología , Radioterapia de Intensidad Modulada/efectos adversos , Neoplasias del Cuello Uterino/radioterapia , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Enfermedad Crónica , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología

RESUMEN

PURPOSE: To report anatomical and functional results of choroidal melanoma treated by protontherapy between 2001 and 2011 and to compare these with data reported in the literature. METHODS: The present study is a retrospective review of the charts of patients presenting with choroidal melanoma, managed at Strasbourg University Medical Center between 2001 and 2011, and receiving protontherapy. Visual acuity and a complete ophthalmologic examination, including intraocular pressure, dilated fundus exam, and ultrasonography with measurement of the major diameter of the tumor, were performed prior to treatment and at various follow-up visits (every six months for five years, then once a year for ten years). The rates and timing of local complications (cataract, rubeosis, retinal detachment, neovascular glaucoma and secondary enucleation) and systemic complications (metastasis) are also reported. RESULTS: Seventy charts were included. Mean age of the treated population was 61.4 ± 15.2 years. Male/female ratio was 1.06. Mean visual acuity, 0.55 ± 0.6 (20/67) on presentation, decreased progressively from month 42. Mean tumor thickness was 5.8 ± 2.8mm and major diameter 11.2 ± 2.9 mm. Decreased tumor thickness was noted beginning at month 12 of follow-up (Anova, P<0.0001), while major diameter remained unchanged over time (P>0.05). The risk of complications (retinal detachment, rubeosis, neovascular glaucoma) was greater between the second and third year. Mean 5-year survival was 87.5%. The rate of secondary enucleation was 8.5%. CONCLUSION: Protontherapy most often allows for preservation of the globe. Visual loss, often significant and permanent, is frequent.

Asunto(s)

Neoplasias de la Coroides/radioterapia , Melanoma/radioterapia , Terapia de Protones , Neoplasias de la Úvea/radioterapia , Centros Médicos Académicos , Anciano , Neoplasias de la Coroides/epidemiología , Neoplasias de la Coroides/patología , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Masculino , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Terapia de Protones/efectos adversos , Resultado del Tratamiento , Carga Tumoral , Neoplasias de la Úvea/epidemiología , Neoplasias de la Úvea/patología

RESUMEN

Exposure to hyperglycemia in utero impairs rat nephrogenesis. The effect of maternal diabetes on insulin-like growth factors and their receptors in the fetal kidney is associated with an increase in both mRNA and protein of the insulin-like growth factor II/mannose 6-phosphate receptor. However, this receptor has never been localized in the fetal kidney. The spatial and temporal distribution of the three insulin-like growth factor receptors (insulin-like growth factor I receptor, insulin-like growth factor II/mannose 6-phosphate receptor and insulin receptor) in rat metanephros during both normal and streptozotocin-induced diabetic renal development was investigated using in situ hybridization and immunohistochemistry. All receptors were found in the fetal kidney from the start of nephrogenesis. Insulin-like growth factor I receptor expression was ubiquitous and continuously present during metanephric development. Insulin receptor expression was developmentally regulated during kidney maturation with an enhanced expression in proximal tubules at the late stages of development. Insulin-like growth factor II/mannose 6-phosphate receptor expression was ubiquitous in the early stages of development and was dramatically decreased at the late stages of normal kidney development. Insulin receptor and insulin-like growth factor I receptor expressions were unchanged in diabetic metanephroi. Although the spatial expression of insulin-like growth factor II/mannose 6-phosphate receptor was unaffected by hyperglycemia, its expression was not downregulated in the mesenchyme of the nephrogenic zone of diabetic fetuses on gestational day 20. This study suggests a crucial role of insulin-like growth factor II/mannose 6-phosphate receptor in the pathogenesis of the impaired nephrogenesis in fetuses of diabetic mothers.

Asunto(s)

Diabetes Mellitus Experimental/complicaciones , Riñón/anomalías , Riñón/metabolismo , Organogénesis/fisiología , Embarazo en Diabéticas/complicaciones , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 2/metabolismo , Receptor de Insulina/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Femenino , Hiperglucemia/complicaciones , Inmunohistoquímica , Riñón/fisiopatología , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 2/genética , Receptor de Insulina/genética

RESUMEN

We have recently demonstrated that the exposure to hyperglycemia in utero impairs nephrogenesis in rat fetuses (Amri K et al., Diabetes 48:2240-2245, 1999). Diabetic pregnancy is commonly associated with alterations in the IGF system in fetal tissues. It has also been shown that both IGF-I and IGF-II are produced within developing metanephros and promote renal organogenesis. Therefore, we investigated the effect of maternal diabetes on IGFs and their receptors in developing fetal rat kidney. Diabetes was induced in pregnant rats by a single injection of streptozotocin on day 0 of gestation. We measured the amounts of IGF and their receptors, both proteins and mRNAs, in the metanephroi of fetuses issued from diabetic subjects and in age-matched fetuses from control subjects (14-20 days of gestation). IGF-II was produced throughout fetal nephrogenesis, whereas IGF-I protein was not detected, suggesting a critical role of IGF-II in kidney development. Fetal exposure to maternal diabetes caused no change in IGF production in the early stages of nephrogenesis. Similarly, the amounts of IGF-I receptor and insulin receptor were not altered. By contrast, there was an increase in production of IGF-II/mannose-6-phosphate receptor throughout nephrogenesis. Because this receptor plays an essential role in regulating the action of IGF-II, the altered nephrogenesis in fetuses exposed to maternal diabetes may be linked to a decrease in IGF-II bioavailability.

Asunto(s)

Diabetes Mellitus Experimental/fisiopatología , Regulación del Desarrollo de la Expresión Génica/fisiología , Riñón/embriología , Embarazo en Diabéticas/fisiopatología , Receptor IGF Tipo 2/genética , Animales , Desarrollo Embrionario y Fetal , Femenino , Edad Gestacional , Factor I del Crecimiento Similar a la Insulina/análisis , Factor II del Crecimiento Similar a la Insulina/análisis , Embarazo , Biosíntesis de Proteínas , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Transcripción Genética

RESUMEN

IGFs and their binding proteins are important regulators of fetal development. We have previously reported that overexpression of the human IGF binding protein-1 in mice is associated with glomerulosclerosis. The aim of this study was to investigate whether, in that model, decreased bioavailability of IGFs also affected nephrogenesis. When the mothers expressed human IGF binding protein-1, pups were growth retarded and had a reduced number of nephrons. Even nontransgenic pups born to heterozygous mothers had a nephron reduction, indicating that renal hypoplasia was secondary to fetal growth retardation. When the transgene was expressed only in the fetus, pups had a normal birth weight and the kidney was normal at birth, as indicated by histologic studies. However, a significant reduction in the nephron number was observed at 3 mo of age. Because nephrogenesis continues for a few days after birth in the mouse, this indicated that human IGF binding protein-1 overexpression altered postnatal nephrogenesis. In addition, exogenously added IGF-II, but not IGF-I, was effective in stimulating in vitro nephrogenesis. Together these elements suggest that reduced amounts of circulating IGFs, presumably IGF-II, impair kidney development.

Asunto(s)

Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Nefronas/embriología , Animales , Animales Recién Nacidos , Femenino , Heterocigoto , Homocigoto , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Ratones , Ratones Transgénicos , Nefronas/anatomía & histología , Embarazo , Ratas , Ratas Sprague-Dawley

RESUMEN

Advances in the molecular biology of retinoids have provided evidence that vitamin A profoundly influences the differentiation of the whole embryo. In addition to its well-characterized role in primary body axis and central nervous system formation, vitamin A is also required for the ad hoc development of numerous tissues and organs, including the kidney. This review will focus on the emerging evidence that the development of the urogenital tract depends on retinoids. In order to understand the role of vitamin A during kidney development, the mechanisms and sites of retinoic acid production are presented. In addition, an overview of the molecular targets that may be regulated by retinoic acid is included. Together, these elements support the concept that control of vitamin A homeostasis during renal organogenesis might control nephrogenesis via specific gene expression. The clinical impact of variations in vitamin A status during pregnancy is discussed.

Asunto(s)

Nefronas/embriología , Retinoides/metabolismo , Animales , Embrión de Mamíferos/fisiología , Desarrollo Embrionario y Fetal/fisiología , Humanos , Sistema Urogenital/embriología

RESUMEN

Regulation of genes involved in fatty acid (FA) utilization in heart and liver of weanling rats was investigated in response to variations in dietary lipid content and to changes in intracellular FA homeostasis induced by etomoxir, a blocker of FA import into mitochondria. Northern-blot analyses were performed using cDNA probes specific for FA transport protein, a cell membrane FA transporter; long-chain- and medium-chain acyl-CoA dehydrogenases, which catalyze the first step of mitochondrial FA beta-oxidation; and acyl-CoA oxidase, a peroxisomal FA beta-oxidation marker. High-fat feeding from postnatal d 21 to 28 resulted in a coordinate increase (58 to 136%) in mRNA abundance of all genes in heart. In liver, diet-induced changes in mitochondrial and peroxisomal beta-oxidation enzyme mRNAs (from 52 to 79%) occurred with no change in FA transport protein gene expression. In both tissues, the increases in mRNA levels went together with parallel increases in enzyme activity. Changes in FA homeostasis resulting from etomoxir administration led to a marked stimulation (76 to 180%) in cardiac expression of all genes together with parallel increases in enzyme activities. In the liver, in contrast, etomoxir stimulated the expression of acyl-CoA oxidase gene only. Feeding rats a low-fat diet containing 0.5% clofibrate, a ligand of peroxisome proliferator-activated receptor alpha, resulted in similar inductions of beta-oxidation enzyme genes in both tissues, whereas up-regulation of FA transport protein gene was restricted to heart. Altogether, these data suggest that changes in FA homeostasis in immature organs resulting either from high-fat diet or beta-oxidation blockade can efficiently be transduced to the level of gene expression, resulting in tissue-specific adaptations in various FA-using enzymes and proteins.

Asunto(s)

Proteínas Portadoras/genética , Ácidos Grasos/metabolismo , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana , Acil-CoA Deshidrogenasa , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Acil-CoA Oxidasa , Animales , Clofibrato/farmacología , Grasas de la Dieta/administración & dosificación , Proteínas de Transporte de Ácidos Grasos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipolipemiantes/farmacología , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Mitocondrias/metabolismo , Miocardio/metabolismo , Oxidación-Reducción , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Peroxisomas/metabolismo , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética

RESUMEN

Several lines of evidence, mostly derived from animal studies, indicate that changes in the fetal environment may affect the renal development. Fetal growth retardation is associated with a nephron deficit in both humans and animals. Changes in the supply of vitamin A to the fetus may be responsible for the variations in the number of nephrons in the human kidney. In utero exposure to hyperglycemia or drugs may also cause a nephron deficit.

Asunto(s)

Ambiente , Riñón/patología , Nefronas/patología , Animales , Femenino , Retardo del Crecimiento Fetal/patología , Gentamicinas/efectos adversos , Humanos , Embarazo , Embarazo en Diabéticas/patología , Deficiencia de Vitamina A/patología

RESUMEN

BACKGROUND: We have previously found that nephron number was not fixed, that is, there was a direct correlation between low birth weight and decreased nephron number in infants. In sclerosis-prone rats, we found that gentamicin exposure in utero induced a reduction in glomerular number and aggravated glomerulosclerosis in adults. In mice, we found that an inborn 50% reduction in nephron number, caused by the Os mutation, was associated with glomerulosclerosis in sclerosis-prone (ROP+/+) mice, but not in sclerosis-resistant (C57BL/6J) mice. Because the genetic background determined the response to decreased nephron number, we asked whether the susceptibility changes in glomerular number and glomerulosclerosis were linked. METHODS: Gentamicin was administered before and after the onset of fetal nephrogenesis. (1) Prior to the onset of nephrogenesis, two groups of pregnant mice were treated from embryonic day (E) E8 to E12. In group A, early glomerular development was studied by placing ureteric ridges removed on E12 in vitro for four days, following which the ureteric bud branches and glomeruli were counted using lectin staining. In group B, nephron number was determined in spontaneously delivered 14-day-old (14PN) pups by counting glomeruli. (2) After the onset of nephrogenesis, to determine the direct effects of gentamicin on nephron induction, ureteric ridges were placed in organ culture at E12 of normal gestation, in the presence or absence of gentamicin. The number of glomeruli and ureteric bud branches were counted after six days in culture. RESULTS: A decrease in glomerular number and ureteric bud branches was observed in sclerosis-prone (ROP+/+) mice, irrespective of whether gentamicin was administered prior to or after the onset of nephrogenesis. Glomerular number and ureteric bud branching were not decreased by gentamicin in sclerosis-resistant (C57BL/6) mice. CONCLUSIONS: These data provide evidence that there is a positive correlation between the susceptibility to glomerulosclerosis in adulthood and a reduction in nephron number in utero. Thus, exposure to nephrotoxins in utero compounds the risk of renal failure as an adult in sclerosis-prone individuals.

Asunto(s)

Feto/efectos de los fármacos , Glomérulos Renales/embriología , Glomérulos Renales/patología , Riñón/efectos de los fármacos , Animales , Femenino , Gentamicinas/toxicidad , Glomérulos Renales/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Embarazo , Esclerosis

RESUMEN

Several lines of evidence, mostly derived from animal studies, indicate that changes in fetal environment may affect renal development. Besides maternal hyperglycemia or drug exposure, that were recently found to alter nephrogenesis, changes in vitamin A supply to the fetus may prove to be responsible for most of the variations in nephron number found in the population. A low vitamin A status in the fetus may be a major cause of inborn nephron deficit, either as a feature of intrauterine growth retardation or independently of growth retardation. The possibility that vitamin A status may also influence renal vascular development is raised. We suggest that low vitamin A supply to the fetus plays a role in the intrauterine programming of chronic renal disease and hypertension.

Asunto(s)

Enfermedades Renales/patología , Riñón/embriología , Nefronas/embriología , Animales , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/patología , Riñón/anomalías , Riñón/efectos de los fármacos , Enfermedades Renales/congénito , Enfermedades Renales/metabolismo , Nefronas/anomalías , Nefronas/efectos de los fármacos , Embarazo , Complicaciones del Embarazo/metabolismo , Complicaciones del Embarazo/patología , Efectos Tardíos de la Exposición Prenatal , Deficiencia de Vitamina A/metabolismo , Deficiencia de Vitamina A/patología

RESUMEN

Congenital malformations occur more frequently in the offspring of diabetic mothers. These in vivo and in vitro studies investigate the potential adverse effects of hyperglycemia on kidney development in the rat. Female rats were made hyperglycemic throughout gestation with a single injection of streptozotocin (STZ) on day 0 of gestation, or for a short period encompassing the early stage of renal organogenesis by infusing glucose from gestational days 12-16. Kidney development in the pups was assessed by determining the total number of nephrons formed in the kidney. The number of nephrons was significantly reduced (10-35%) in the pups from STZ-treated dams, as a function of hyperglycemia. There were also fewer nephrons in pups from dams given glucose infusion whose hyperglycemia was transiently higher on day 13 of gestation. The in vitro experiments were done on metanephroi removed from 14-day-old fetuses and grown for 6 days in medium containing 0, 6.9, 13.8, or 27.5 mmol/l glucose. The development of explants grown in 0, 13.8, and 27.5 mmol/l glucose was impaired compared with that of explants grown in the 6.9 mmol/l control medium, showing that the glucose concentration must be closely controlled to ensure optimum in vitro metanephros development. Thus, exposure to hyperglycemia in utero can cause a nephron deficit, which in turn may have renal consequences later in life.

Asunto(s)

Diabetes Mellitus Experimental/fisiopatología , Hiperglucemia/fisiopatología , Riñón/embriología , Riñón/crecimiento & desarrollo , Embarazo en Diabéticas/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Envejecimiento , Animales , Animales Recién Nacidos , Peso al Nacer , Glucemia/metabolismo , Peso Corporal , Desarrollo Embrionario y Fetal , Femenino , Hiperglucemia/etiología , Insulina/sangre , Nefronas/anatomía & histología , Tamaño de los Órganos , Embarazo , Ratas , Ratas Sprague-Dawley

RESUMEN

During late pregnancy, the fetal lung stores surfactant in preparation for extrauterine life. Surfactant deficiency, most often due to prematurity, precipitates respiratory distress syndrome (RDS) of the neonate. Although vitamin A (retinol) and retinoic acid have been shown to enhance the synthesis of phospholipid surfactant components, their effect on surfactant-specific proteins is unclear. No attempt has been made to evaluate the consequences of vitamin A restriction on surfactant phospholipid storage or on the expression of the life-essential surfactant protein-B (SP-B). We induced in rats a partial vitamin A deficiency leading to a 30-60% reduction in blood retinol, a status compatible with maintenance of gestation and absence of gross abnormalities in offspring. At term, lung surfactant phospholipids were reduced by 21%, and the major surfactant phospholipid, disaturated phosphatidylcholine (DSPC), was reduced by 27% in vitamin A-deficient (VAD) fetuses. The decrease in surfactant phospholipids and DSPC correlated linearly with plasma retinol, and reached about 50% in fetuses with the lowest retinol concentrations; it was accompanied by reduced expression of the gene for fatty acid synthase, a key enzyme in the synthetic pathway for surfactant-phospholipid lipid precursors. The amounts of SP-A, SP-B, and SP-C messenger RNAs were decreased by 46%, 32%, and 28%, respectively, in VAD fetuses. Consistently, amounts of SP-A and SP-B proteins were diminished as assessed by Western blotting. The proportion of type II cells determined after SP-B labeling was unchanged in VAD as compared with control lungs. Vitamin A deficiency is therefore a cause of lung maturational delay. In view of its rather large incidence in human populations, it may represent an increased risk for RDS and an aggravating factor for prematurity.

Asunto(s)

Pulmón/embriología , Complicaciones del Embarazo , Preñez , Deficiencia de Vitamina A/embriología , Animales , Citidililtransferasa de Colina-Fosfato/análisis , Diterpenos , Femenino , Pulmón/enzimología , Fosfolípidos/análisis , Embarazo , Surfactantes Pulmonares/análisis , Ratas , Ratas Sprague-Dawley , Ésteres de Retinilo , Vitamina A/análogos & derivados , Vitamina A/análisis , Vitamina A/sangre

Asunto(s)

Nefronas/fisiopatología , Animales , Peso al Nacer/fisiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Hipertensión/fisiopatología , Nefronas/efectos de los fármacos , Vitamina A/fisiología

RESUMEN

Vitamin A closely modulates nephron endowment at birth. It is also required for the development of renal vasculature. Fetal vitamin A status may thus be responsible for most of the variations in nephron number found in the general population, and may play a major role in the intrauterine programming of chronic renal disease and hypertension.

Asunto(s)

Riñón/embriología , Riñón/fisiología , Retinoides , Vitamina A/fisiología , Animales , Humanos , Enfermedades Renales/fisiopatología

RESUMEN

Vitamin A and its derivatives have been shown to promote kidney development in vitro in a dose-dependent fashion. To address the molecular mechanisms by which all-trans-retinoic acid (RA) may regulate the nephron mass, rat kidneys were removed on embryonic day 14 (E14) and grown in organ culture under standard or RA-stimulated conditions. By using RT-PCR, we studied the expression of the glial cell line-derived neurotrophic factor (GDNF), its cell surface receptor-alpha (GDNFR-alpha), and the receptor tyrosine kinase c-ret, known to play a major role in renal organogenesis. Expression of GDNF and GDNFR-alpha transcripts was high at the time of explantation and remained unaffected in culture with or without RA. In contrast, c-ret mRNA level, which was low in E14 metanephros and dropped rapidly in vitro, was increased by RA in a dose-dependent manner. The same is true at the protein level. Exogenous GDNF barely promotes additional nephron formation in vitro. Thus the present data establish c-ret as a key target of retinoids during kidney organogenesis.

Asunto(s)

Proteínas de Drosophila , Feto/metabolismo , Riñón/embriología , Factores de Crecimiento Nervioso , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Tretinoina/fisiología , Secuencia de Aminoácidos/genética , Animales , Secuencia de Bases/genética , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario y Fetal/fisiología , Feto/fisiología , Factor Neurotrófico Derivado de la Línea Celular Glial , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Técnicas de Cultivo de Órganos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ret , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/genética , Tretinoina/farmacología

RESUMEN

BACKGROUND: Vitamin A plays a critical role in fetal organogenesis, and its severe deficiency during pregnancy is known to result in malformations of several organs, including the kidney. However, the consequences of mild vitamin A deficiency (VAD) has received little attention. In the present study, we examined the effect of in utero exposure to mild VAD on renal organogenesis. METHODS: A rat model of mild VAD compatible with normal gestation was developed. Plasma retinol was determined by reverse phase HPLC in mothers and fetuses. Nephron counting was performed in kidneys of fetuses and pups issued from control and VAD mothers. Metanephroi explanted from 14-day-old fetuses from both groups were cultured in the presence or absence of retinoic acid (RA), and growth and differentiation were assessed. c-ret expression was analyzed from fetuses exposed in utero to VAD or to normal vitamin A status and also in metanephroi grown in culture with or without RA using RT-PCR. RESULTS: The 50% reduction in circulating vitamin A levels induced by vitamin A deprivation in pregnant rats did not affect the overall fetal development. However, the number of nephrons was reduced by 20% in 21-day-old VAD fetuses. The number of nephrons was closely correlated with circulating vitamin A level in both VAD and control fetuses. Metanephroi taken from VAD fetuses developed to a lesser extent in vitro, but their capacity to respond to exogenous retinoic acid was not altered. Finally, we found that the expression of the proto-oncogene c-ret was modulated according to the retinoid environment. CONCLUSION: We conclude that vitamin A supply to the fetus is critical in determining the number of nephrons. Data available thus far on the frequency of mild VAD during pregnancy and on the long-term consequences of inborn nephron deficit highlight the clinical relevance of the present study.

Asunto(s)

Proteínas de Drosophila , Nefronas/anomalías , Deficiencia de Vitamina A/complicaciones , Animales , Femenino , Embarazo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ret , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/genética , Vitamina A/sangre

RESUMEN

This study examines the ability of dietary lipids to regulate gene expression of mitochondrial and peroxisomal fatty acid beta-oxidation enzymes in the kidney cortex and medulla of 3-wk-old rats and evaluates the role of glucagon or of the alpha-isoform of peroxisome proliferator-activated receptor (PPARalpha) in mediating beta-oxidation enzyme gene regulation in the immature kidney. The long-chain (LCAD) and medium-chain acyl-CoA dehydrogenases (MCAD) and acyl-CoA oxidase (ACO) mRNA levels were found coordinately upregulated in renal cortex, but not in medulla, of pups weaned on a high-fat diet from day 16 to 21. Further results establish that switching pups from a low- to a high-fat diet for only 1 day was sufficient to induce large increases in cortical LCAD, MCAD, and ACO mRNA levels, and gavage experiments show that this upregulation of beta-oxidation gene expression is initiated within 6 h following lipid ingestion. Treatment of pups with clofibrate, a PPARalpha agonist, demonstrated that PPARalpha can mediate regulation of cortical beta-oxidation enzyme gene expression, whereas glucagon was found ineffective. Thus dietary lipids physiologically regulate gene expression of mitochondrial and peroxisomal beta-oxidation enzymes in the renal cortex of suckling pups, and this might involve PPARalpha-mediated mechanisms.

Asunto(s)

Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/metabolismo , Corteza Renal/metabolismo , Médula Renal/metabolismo , Oxidorreductasas/metabolismo , Acil-CoA Deshidrogenasa , Acil-CoA Oxidasa , Animales , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Corteza Renal/crecimiento & desarrollo , Médula Renal/crecimiento & desarrollo , Ratas , Ratas Wistar

RESUMEN

Global management of drug safety data is the best way to make the detection and validation of adverse drug reactions (ADRs) earlier. Centralization needs a previous standardization, of which terminology is a crucial component. ADR terminology must be designed so as to enable users to know exactly what is covered by each term regarding the nature of the reaction and its significance for public health. A worldwide standardized terminology for all drug reporting purposes is currently being developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. However, practical definitions of medical terms will be necessary and could be developed by specialists on drug safety in collaboration with specialists of different system organs, as has already been achieved for some of them.

Asunto(s)

Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Terminología como Asunto , Guías como Asunto , Humanos

RESUMEN

During development, gene expression of medium-chain acyl-CoA dehydrogenase (MCAD), a nuclear-encoded mitochondrial enzyme that catalyses the first step of medium-chain fatty acid beta-oxidation, is highly regulated in tissues in accordance with fatty acid utilization, but the factors involved in this regulation are largely unknown. To investigate a possible role of thyroid hormones, rat pups were made hypothyroid by the administration of propylthiouracyl to the mother from day 12 of gestation, and their kidneys, heart and liver were removed on postnatal day 16 to determine MCAD mRNA abundance, protein level and enzyme activity. Similar experiments were run in 3,3',5-tri-iodothyronine (T3)-replaced hypothyroid (1 microg of T3/100 g body weight from postnatal day 5 to 15) and euthyroid pups. Hypothyroidism led to an increase in MCAD mRNA abundance in kidney and a decrease in abundance in heart, but had no effect in liver. The protein levels and enzyme activity were lowered in hypothyroid heart and kidney, suggesting that hypothyroidism affects post-transcriptional steps of gene expression in the kidney. All the effects of hypothyroidism were completely reversed in both heart and kidney by T3 replacement. Injection of a single T3 dose into 16-day-old euthyroid rats also led to tissue-specific changes in mRNA abundance. Nuclear run-on assays performed from hypothyroid and hypothyroid plus T3 rats showed that T3 stimulates MCAD gene transcription in heart and represses it in the kidney. These results indicate that the postnatal rise in circulating T3 is essential to the developmental regulation of the MCAD gene in vivo.

Asunto(s)

Acil-CoA Deshidrogenasas/biosíntesis , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Hipotiroidismo/enzimología , Efectos Tardíos de la Exposición Prenatal , Triyodotironina/farmacología , Acil-CoA Deshidrogenasa , Animales , Núcleo Celular/metabolismo , Femenino , Corazón/efectos de los fármacos , Corteza Renal/efectos de los fármacos , Corteza Renal/enzimología , Hígado/efectos de los fármacos , Hígado/enzimología , Miocardio/enzimología , Embarazo , Propiltiouracilo , Ratas , Ratas Wistar , Valores de Referencia , Triyodotironina/sangre

RESUMEN

In the proximal convoluted tubule (PCT) of rat kidney, reabsorption is known to take place during fetal life, but no data on Na-K-ATPase and mitochondrial energy metabolism enzymes in this epithelium were available at fetal and neonatal stages. With use of the quantitative histochemistry approach, Na-K-ATPase, citrate synthase (tricarboxylic acid cycle), 3-ketoacid CoA-transferase and thiolase (ketone body oxidation), beta-hydroxyacyl-CoA dehydrogenase (fatty acid oxidation), and acetylcarnitine transferase (acetyl-CoA transport through mitochondrial membrane) were microassayed in PCT and metanephric mesenchyme of fetal and newborn rat kidney. The data indicate that, during fetal life, PCT differentiation involves concomitant increases in Na-K-ATPase and oxidative enzyme activities, supporting the hypothesis that mitochondria could play an active role in cellular ATP turnover when reabsorptive functions develop. Birth resulted in marked increases in the activities of Na-K-ATPase and of fatty acid and ketone body oxidation enzymes in the PCT, whereas no changes in enzyme activities occurred in the metanephric mesenchyme between the fetal and the newborn stage.

Asunto(s)

Túbulos Renales Proximales/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Acetil-CoA C-Acetiltransferasa/metabolismo , Animales , Animales Recién Nacidos , Carnitina O-Acetiltransferasa/metabolismo , Coenzima A Transferasas/metabolismo , Metabolismo Energético , Túbulos Renales Proximales/enzimología , Oxidación-Reducción , Ratas , Ratas Wistar