RESUMEN
Prostaglandins (PGs), especially PGE(2), are involved in the hypothalamic control of gonadotrophin-releasing hormone (GnRH) release, acting at least in part on the terminal of GnRH axons in the median eminence. The present study aimed: (i) to clarify the role of PG(s) in regulating GnRH cell function at the level of the perikarya in the preoptic area; (ii) to determine the cyclooxygenase (COX) isozyme responsible for producing PG(s) that regulates GnRH perikarya; and (iii) to identify cell types that contain the responsible COX isozyme in female rats. A surge of luteinising hormone (LH) secretion was induced by oestrogen and progesterone in ovariectomised rats. Treatment of the rat before the LH surge with indomethacin, a nonselective COX inhibitor, or NS-398, a selective COX-2 inhibitor, did not interfere with the surge. However, treatment with indomethacin or flurbiprofen, a selective COX-1 inhibitor, significantly reduced the number of GnRH-immunoreactive cells in the preoptic area at the time of peak LH secretion during the surge. NS-398 did not affect the GnRH immunoreactivity. Double-labelled immunofluorescent histochemistry revealed COX-1 immunoreactivity in the vicinity of, but not within, GnRH containing neurones in the preoptic area. COX-2 immunoreactivity was not found in the same area. The COX-1 immunoreactivity was almost entirely localised in microglia in the preoptic area, but not in neurones or astrocytes. These results suggest that microglia in the preoptic area containing COX-1 are responsible for producing PG(s), which, in turn, facilitates the accumulation of GnRH during the gonadotrophin surge in female rats.
Asunto(s)
Ciclooxigenasa 1/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Proteínas de la Membrana/metabolismo , Microglía/fisiología , Área Preóptica/fisiología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Estrógenos/metabolismo , Femenino , Flurbiprofeno/farmacología , Indometacina/farmacología , Hormona Luteinizante/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Microglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Nitrobencenos/farmacología , Ovariectomía , Área Preóptica/efectos de los fármacos , Progesterona/metabolismo , Ratas , Ratas Wistar , Sulfonamidas/farmacología , Factores de TiempoRESUMEN
Administration of ferric nitrilotriacetate (Fe-NTA) in vivo causes acute renal tubular injury and finally induces renal cell carcinoma. There is accumulating evidence that these processes involve free radicals generated by Fe-NTA. To study the mechanism of renal carcinogenesis by Fe-NTA, we attempted to induce malignant transformation of primary cultured renal cells by treatment with Fe-NTA. When primary cultured renal cells (PRC) were treated continuously with Fe-NTA, all of the PRC died without transformation. On the other hand, when PRC were treated intermittently with Fe-NTA, transformed epithelial colonies were observed at 3 weeks after the first treatment. The established transformed cell line (RK523) showed drastic morphological transformation, grew in soft agar, and formed tumors when transplanted into athymic nude mice. These results indicate that the balance between cytotoxicity and mutagenecity is important for Fe-NTA induced transformation. The RK523 cell line may be a useful model for studying renal carcinogenesis in vitro.