RESUMEN
CONTEXT: Primary adrenal Cushing's syndrome can result from the aberrant adrenal expression of several hormone receptors; this mechanism has not been explored in detail in aldosterone-producing tumors. OBJECTIVE: The objective of the study was to evaluate a 56-yr-old male patient with an aldosteronoma for the regulation of aldosterone secretion by aberrant hormone receptors. RESULTS: Renin-independent stimulation of aldosterone secretion was observed in vivo after a mixed meal, oral glucose, or administration of glucose-dependent insulinotropic peptide (GIP), vasopressin, and tegaserod. The mixed meal-mediated stimulation of aldosterone was not present in five other cases of aldosteronoma. A smaller response of aldosterone after GIP infusion was observed in a normal subject. Aldosterone secretion was stimulated by GIP in primary cultures of this patient's aldosteronoma. Increased expression of GIP receptor was found in this aldosteronoma by real-time RT-PCR and immunohistochemistry. The GIP receptor protein was also found at lower levels in zona glomerulosa cells of the normal adjacent adrenal gland. Increased expression of serotonin 4 and ACTH receptors was also present in this aldosteronoma. CONCLUSIONS: This case report provides new evidence of the implication of aberrant hormone receptors in the regulation of this aldosteronoma and suggests that further detailed studies of the role of aberrant hormone receptors in this frequent pathology should be undertaken.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Aldosterona/metabolismo , Receptores de la Hormona Gastrointestinal/fisiología , Hormona Adrenocorticotrópica/farmacología , Polipéptido Inhibidor Gástrico/farmacología , Humanos , Masculino , Persona de Mediana Edad , Receptores de Corticotropina/fisiología , Receptores de la Hormona Gastrointestinal/análisis , Receptores de Serotonina 5-HT4/fisiología , Receptores de Vasopresinas/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Acute allograft glomerulopathy (AAG) is a distinct form of allograft rejection characterized by cytotoxic T-cell-mediated injury to the renal glomerular and arteriolar endothelium. Acute allograft glomerulopathy is characterized by mononuclear cell infiltration of glomerular capillary tufts in association with endothelial cell hypertrophy and injury. Intra-glomerular thrombi have been described in AAG, suggesting that overlapping features of AAG and post-transplant thrombotic microangiopathy (TMA) may coexist. We present a case suggesting that complement factor H deficiency, a known hereditary risk factor for TMA, may also favor development of AAG. We discuss the potential implications of factor H deficiency in the pathophysiology of renal allograft microvascular injury, leukocyte infiltration and formation of intraglomerular platelet thrombi. We propose that unopposed complement activation is a risk factor for both immune and nonimmune forms of microvascular injuries in renal allografts.
Asunto(s)
Lesión Renal Aguda/cirugía , Factor H de Complemento/deficiencia , Síndrome Hemolítico-Urémico/patología , Glomérulos Renales/patología , Trasplante de Riñón/patología , Enfermedad Aguda , Adulto , Biopsia con Aguja , Cadáver , Creatinina/sangre , Femenino , Humanos , Complicaciones Posoperatorias/patología , Reoperación , Donantes de Tejidos , Trasplante Homólogo/patologíaRESUMEN
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent adrenal Cushing's syndrome (CS), which is often associated with Carney complex (CNC). We have recently described a paradoxical increase in cortisol excretion after dexamethasone administration in most patients with PPNAD. In the present study we investigated the hypothesis that this phenomenon is due to a primary abnormality of the tissues affected by PPNAD, rather than a defect of the patients' hypothalamic-pituitary-adrenal axis; as such it should be replicated in vitro by adrenal slices exposed directly to dexamethasone. We were able to study adrenal tissues from eight patients with CS caused by PPNAD; two patients were also studied in vivo according to a protocol first described in ACTH-independent macronodular adrenal hyperplasia (AIMAH) for the clinical detection of aberrant hormone receptor expression. Their DNA has been previously screened for inactivating mutations of the PRKAR1A gene, the most frequent molecular defect leading to PPNAD and/or CNC. We also investigated whether glucocorticoid receptor (GR) expression underlies paradoxical dexamethasone responses in PPNAD by immunohistochemistry and semiquantitative PCR, and we correlated GR expression with that of other markers for PPNAD (e.g. synaptophysin). Indeed, we demonstrated that dexamethasone induced cortisol secretion in vitro in five of these tumors; no such increase was seen in adenomatous or AIMAH tissues that were treated in the same manner. GR mRNA was expressed, and GR immunoreactivity was detected in PPNAD nodular cells. Staining for GR was not seen in surrounding cortical cells, and hence, it correlated with synaptophysin, which also stains PPNAD in a similar manner. In normal adrenal tissue, GR was detected mostly in medullary areas, whereas GR immunoreactivity was weak in adenomatous and AIMAH tissues. We conclude that 1) dexamethasone produces an increase in glucocorticoid synthesis by PPNAD adrenal slices in vitro, suggesting a direct effect on adrenocortical tissue, and 2) this phenomenon is accompanied by increased expression of the GR in PPNAD nodules. PPNAD and/or CNC patients with and without mutations leading to protein kinase A activation demonstrated in vitro and/or in vivo paradoxical dexamethasone responses and GR expression, indicating that PRKAR1A alterations are not necessary for these phenomena.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/metabolismo , Síndrome de Cushing/metabolismo , Dexametasona/farmacología , Glucocorticoides/farmacología , Hidrocortisona/metabolismo , Receptores de Glucocorticoides/biosíntesis , Actinas/biosíntesis , Adenoma/metabolismo , Adolescente , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/patología , Médula Suprarrenal/metabolismo , Médula Suprarrenal/patología , Adulto , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Masculino , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estimulación QuímicaRESUMEN
We recently identified a novel calcium-regulated gene, HCaRG, that is highly expressed in the kidney and maps to a chromosomal locus determining kidney weight in rats. The mRNA levels of HCaRG negatively correlate with the proliferative status of the kidney cells. To investigate its role in renal epithelial cellular growth directly, we studied the human embryonic kidney cell line (HEK-293) stably transfected with either plasmid alone or plasmid containing rat HCaRG. [(3)H]thymidine incorporation was significantly lower in HCaRG clones. Although HCaRG clones exhibited some enhanced susceptibility to cell death, this was not the primary mechanism of reduced proliferation. Cell cycle analysis revealed a G(2)M phase accumulation in HCaRG clones that was associated with upregulation of p21(Cip1/WAF1) and downregulation of p27(Kip1). HCaRG clones had a greater protein content, larger cell size, and released 4.5- to 8-fold more of an atrial natriuretic peptide-like immunoreactivity compared with controls. In addition, HCaRG clones demonstrated the presence of differentiated junctions and a lower incidence of mitotic figures. Genistein treatment of wild-type HEK-293 cells mimicked several phenotypic characteristics associated with HCaRG overexpresssion, including increased cell size and increased release of atrial natriuretic peptide. Taken together, our results suggest that HCaRG is a regulator of renal epithelial cell growth and differentiation causing G(2)M cell cycle arrest.
Asunto(s)
Diferenciación Celular/fisiología , Células Epiteliales/metabolismo , Riñón/citología , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Factor Natriurético Atrial/biosíntesis , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Tamaño de la Célula/efectos de los fármacos , Tamaño de la Célula/fisiología , Células Clonales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Ciclinas/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Fase G2/efectos de los fármacos , Fase G2/fisiología , Perfilación de la Expresión Génica , Humanos , Mitosis/efectos de los fármacos , Mitosis/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/farmacología , ARN Mensajero/metabolismo , Ratas , Transfección , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
This report describes the light microscopic (LM), immunohistochemical (IHC), and electron microscopic (EM) features of a multifocal, nascent, and invasive myoepithelial carcinoma of the breast. By LM, the spindle cells disclosed fibrillar acidophilic cytoplasm, mild nuclear atypia, and a low mitotic index. Myoepithelial differentiation was established through IHC (single- and double-labeling techniques) and EM: periductal and infiltrating spindle cells coexpressed total muscle actin, alpha-smooth muscle actin, vimentin, cytokeratin 14, and pankeratin, and their EM features were characteristic of myoepithelial cells, i.e., perinuclear tonofilaments, subplasmalemmal bundles of microfilaments with dense bodies, intermediate junctions, poorly developed desmosomes, pinocytic vesicles, and fragmented external lamina. No invasive epithelial cells disclosed luminal differentiation (by LM, IHC, EM), identifying, thus, this neoplasm as a pure spindle cell myoepithelial carcinoma of the breast.