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Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy

SCIENCE 2000年第5476期289卷 119-123页

作者： Geller, DS Farhi, A Pinkerton, N Fradley, M Moritz, M Spitzer, A Meinke, G Tsai, FTF Sigler, PB Lifton, RP Yale Univ Sch Med Boyer Ctr Mol Med Howard Hughes Med Inst New Haven CT 06510 USA Yale Univ Sch Med Boyer Ctr Mol Med Dept Genet New Haven CT 06510 USA Yale Univ Sch Med Boyer Ctr Mol Med Dept Internal Med Nephrol New Haven CT 06510 USA Yale Univ Sch Med Boyer Ctr Mol Med Dept Mol Biophys & Biochem New Haven CT 06510 USA Yeshiva Univ Albert Einstein Coll Med Dept Pediat Bronx NY 10461 USA

Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.

关键词：醛固酮/代谢氨基酸序列氨基酸取代碱基序列结合竞争性二聚作用杂合子高血压/病因学高血压/遗传学高血压/代谢模型分子分子序列数据系谱点突变妊娠并发症心血管/病因学妊娠并发症心血管/代谢孕酮/代谢蛋白质构象蛋白质结构二级受体盐皮质激素/化学受体盐皮质激素/遗传学受体盐皮质激素/代谢受体类固醇/化学受体类固醇/代谢甾类/代谢青少年女(雌)性人类男(雄)性妊娠

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A single amino acid mutation of Ala-773 in the mineralocorticoid receptor confers agonist properties to 11β-substituted spirolactones

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MOLECULAR PHARMACOLOGY 2000年第4期58卷 684-691页

作者： Auzou, G Fagart, J Souque, A Hellal-Lévy, C Wurtz, JM Moras, D Rafestin-Oblin, ME INSERM U439 F-34090 Montpellier France Inst Genet & Biol Mol & Cellulaire Illkirch CU Strasbourg France Fac Med Xavier Bichat Inst Federatif Rech 02 INSERM U478 Paris France

Sequence analysis revealed a strong homology between the ligand-binding domain (LBD) of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR). Nevertheless, steroids with bulky C11-substituents bind to hGR, unlike hMR. In this report, a mutant hMR, in which the residue Ala-773 facing the C11 steroid position was replaced by a glycine (A773G), was assayed for its capacity to bind steroids, to interact with receptor coactivators, and to stimulate transcription. The capacity of A773G to bind aldosterone and C11-substituted spirolactones was the same as that of the wild-type receptor. The agonist properties of aldosterone, as well as the antagonist feature of compounds bearing a 11 beta-allenyl group and a C17-ketone function, remain unchanged. In contrast, C11-substituted steroids with a 17 gamma-lactonic ring displayed antagonist properties with hMR and acted as potent agonists with A773G. An agonist-dependent hMR interaction with SRC-1 was observed for both the wild-type and the mutant receptors. The hMR activation process is discussed in the light of the hMR-LBD homology model based on the structural data of the human progesterone receptor LBD.

关键词：丙氨酸/遗传学丙氨酸/代谢氨基酸序列氨基酸取代 COS细胞组蛋白酰基转移酶模型分子分子序列数据诱变定点核受体共激活因子1 受体盐皮质激素/激动剂受体盐皮质激素/遗传学受体盐皮质激素/代谢序列同源性氨基酸螺内酯/类似物和衍生物螺内酯/药理学转录因子/代谢转录激活动物人类

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Targeted oncogenesis reveals a distinct tissue-specific utilization of alternative promoters of the human mineralocorticoid receptor gene in transgenic mice

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第11期275卷 7878-7886页

作者： Le Menuet, D Viengchareun, S Penfornis, P Walker, F Zennaro, MC Lombès, M Fac Xavier Bichat INSERM U478 Inst Federatif Rech Cellules Epitheliales F-75870 Paris 18 France Hop Bichat Claude Bernard Serv Anatomopathol F-75018 Paris France

The human mineralocorticoid receptor (hMR) is a nuclear receptor mediating aldosterone action, whose expression is driven by two alternative promoters, P1 and P2, flanking the two first 5'-untranslated exons. In vivo characterization of hMR regulatory regions was performed by targeted oncogenesis in mice using PI or Pa directing expression of the large T antigen of SV40 (TAg). While transgenic *** founders rapidly developed lethal hibernomas from brown fat, cerebral primitive neuroectodermal tumors and facial leiomyosarcomas occurred in *** mice. Quantitative analyses of mouse MR (mMR) and transgene expression indicate that P1 promoter was transcriptionally active in all MR-expressing tissues, directing strong TAg expression in testis and salivary glands, moderate in lung brain, uterus, liver, and heart but, unlike mMR, rather low in colon and kidney. Importantly, the renal transgene expression colocalized with mMR in the distal nephron. In contrast, P2 promoter was approximately 10 times less potent than P1, with no activity in the brain and colon. Several immortalized cell lines were established from both neoplastic and normal tissues of transgenic mice. These cells exhibited differentiated characteristics and maintained MR expression, thus providing useful models for further studies exploring the widespread expression and functions of MR. Our results demonstrate that hMR gene expression in vivo is controlled by complex regulatory mechanisms involving distinct tissue-specific utilization of alternative promoters.

关键词：脂肪组织棕色/病理学抗原病毒肿瘤/遗传学脑/病理学细胞转化肿瘤/遗传学基因表达调控肿瘤平滑肌肉瘤/遗传学平滑肌肉瘤/病理学脂肪瘤/遗传学脂肪瘤/病理学小鼠转基因盐皮质激素类/代谢神经外胚瘤/遗传学神经外胚瘤/病理学表型启动区遗传 RNA 信使/分析受体盐皮质激素/遗传学受体盐皮质激素/代谢信号传导猴病毒40 组织分布动物人类小鼠

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Mechanism of action of the potent sodium-retaining steroid 11,19-oxidoprogesterone

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MOLECULAR PHARMACOLOGY 2000年第1期58卷 58-70页

作者： Galigniana, MD Vicent, GP Piwien-Pilipuk, G Burton, G Lantos, CP Univ Buenos Aires Fac Ciencias Exactas & Nat Dept Quim Biol RA-1053 Buenos Aires DF Argentina Univ Buenos Aires Fac Ciencias Exactas & Nat Dept Quim Organ RA-1053 Buenos Aires DF Argentina Ciudad Univ Consejo Nacl Invest Cient & Tecn Program Regulac Hormonal & Metab Buenos Aires DF Argentina

We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11,19-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19-oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19-oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone.

关键词：醛固酮/药理学抗真菌药/药理学结合竞争性生物转运/药物作用细胞核/药物作用细胞核/代谢药物拮抗作用 HSP90热休克蛋白质类/代谢肾/药物作用肾/代谢赖氨酸/化学代谢清除率分子构象孕酮/类似物和衍生物孕酮/拮抗剂和抑制剂孕酮/药代动力学孕酮/药理学吡喃类大鼠 Sprague-Dawley 受体盐皮质激素/化学受体盐皮质激素/代谢受体类固醇/化学钠/代谢螺环化合物螺内酯/药理学动物男(雄)性大鼠

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Two inbred strains of rats, Fischer 344 and Lewis, showed differential behavior and brain expression of corticosterone receptor mRNA induced by methamphetamine

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NEUROBIOLOGICAL MECHANISMS OF DRUGS OF ABUSE: COCAINE, IBOGAINE, AND SUBSTITUTED AMPHETAMINES 2000年第1期914卷 33-45页

作者： Numachi, Y Yoshida, S Toda, S Matsuoka, H Sato, M Tohoku Univ Grad Sch Med Dept Psychiat Sendai Miyagi 9808574 Japan Univ Michigan Mental Hlth Res Inst Ann Arbor MI 48109 USA

Recently, a role of the hypothalamo-pituitary-adrenocortical (HPA) axis in facilitating the behavioral and neurochemical effects of psychostimulants has been proposed. Two inbred strains of rats, Fischer 344/N (F344) and Lewis/N (LEW), have markedly different HPA axes as well as behavioral responses to psychostimulants: F344 rats show hyperresponsive BPA axis and no significant sensitization to cocaine, whereas LEW rats display blunted response in HPA axis and develop cocaine-induced locomotor sensitization. Corticosterone exerts its biological effects via intracellular receptors, termed type I (mineralocorticoid receptor: MR) and type II (glucocorticoid receptor: GR). The present study examines the development of stereotypy sensitization and the brain expression of mRNAs for MR, GR, and heat shock protein 90 (HSP90) in methamphetamine (MAP)-treated F344 and LEW rats. Animals received i.p. injections with chronic saline (SAL: once daily for 21 days), chronic saline and acute MAP (AM: saline for 20 days and 4 mg/kg MAP on the 21st day), or chronic MAP (CM: 4 mg/kg MAP for 21 days) and were sacrificed three hours after the last injections. Striatum, hippocampus, and cerebellum were quickly dissected on ice and total RNA was isolated for northern analyses. LEW rats developed stereotypy sensitization significantly earlier than F344 rats. AM significantly decreased GR and MR mRNA expression in hippocampus of LEW, compared to SAL. CM significantly increased GR and MR mRNA expression in striatum of F344 compared to SAL and AM, while it decreased GR mRNA in striatum of LEW and MR mRNA in hippocampus, compared to SAL. AM significantly increased HSP90 mRNA in all brain regions examined, without the hippocampus in LEW. CM significantly increased the expression of HSP90 mRNA in the striatum and cerebellum of F344, but significantly decreased in the striatum and hippocampus of LEW. These contrasting differences between F344 and LEW, in their susceptibility to stereotypy sensitiz

关键词：行为动物/药物作用印迹法 RNA/方法体温/药物作用脑/解剖学和组织学脑/药物作用脑/代谢中枢神经系统刺激剂/投药和剂量用药计划表基因表达/药物作用 HSP90热休克蛋白质类/遗传学 HSP90热休克蛋白质类/代谢甲基苯丙胺/投药和剂量大鼠近交F344 大鼠近交Lew 受体糖皮质激素/遗传学受体糖皮质激素/代谢受体盐皮质激素/遗传学受体盐皮质激素/代谢受体类固醇/遗传学受体类固醇/代谢种特异性刻板行为/药物作用时间因素动物男(雄)性大鼠

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Inhibition by aldosterone of insulin receptor mRNA levels and insulin binding in U-937 human promonocytic cells

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JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 1999年第4-6期70卷 211-218页

作者： Campión, J Maestro, B Mata, F Dávila, N Carranza, MC Calle, C Univ Complutense Fac Med Dept Bioquim & Biol Mol E-28040 Madrid Spain Univ Complutense Fac Ciencias Dept Bioquim & Biol Mol E-28040 Madrid Spain Hosp Puerta de Hierro Serv Endocrinol Madrid 28040 Spain

The effect of aldosterone on insulin receptor (IR) expression was investigated in U-937 human promonocytic cells. The putative involvement of the mineralocorticoid receptor (MR) was also analysed. Aldosterone binding assays indicated the presence of MRs with high affinity and limited capacity in these cells. RNA blot assays showed that aldosterone treatment decreased the levels of the two major IR mRNAs (II and 8.5 kb) present in these cells in a dose- and time-dependent manner. The partial reversal of such a decrease by the mineralocorticoid antagonist spironolactone suggested that MR was involved in the process. Experiments with the RNA synthesis inhibitor actinomycin D indicated that the decrease in IR mRNA content in aldosterone-treated cells was not the result of transcript destabilisation. The inhibitory action of aldosterone was not prevented by the simultaneous presence of the protein synthesis inhibitor cycloheximide, suggesting that the reduction of IR gene expression occurs as a direct response to the action of aldosterone. Furthermore, insulin binding assays showed that aldosterone decreased IR capacity but did not alter receptor affinity. In addition, the IR turnover resulted unaltered. These results provide the first evidence for an in vitro modulation of human IR expression by aldosterone. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：醛固酮/代谢醛固酮/药理学结合竞争性放线菌酮/药理学基因表达调控肿瘤/药物作用胰岛素/代谢动力学 RNA 信使/遗传学 RNA 信使/代谢受体胰岛素/遗传学受体胰岛素/代谢受体盐皮质激素/代谢转录遗传/药物作用 U937细胞人类

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Evidence for change of 11β-hydroxysteroid dehydrogenase activity during infancy and childhood

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PEDIATRIC RESEARCH 2000年第5期48卷 697-700页

作者： Dötsch, J Hohenberger, I Peter, M Sippell, W Dörr, HG Univ Erlangen Nurnberg Dept Pediat D-91054 Erlangen Germany Univ Kiel Dept Pediat D-24105 Kiel Germany

The conversion of cortisol (F) to cortisone (E) is catalyzed by 11 beta -hydroxysteroid dehydrogenase type 2. The present study was designed to investigate the changes of F and E plasma concentration as an indirect measurement of 11 beta -hydroxysteroid dehydrogenase activity in infancy and childhood. Plasma samples were obtained from 262 healthy children and adolescents aged 1 d to 18 y. Plasma F and E were measured, using specific radioimmunoassays after extraction and automated Sephadex LH 20 chromatography. The F/E ratio was calculated to assess 11 beta -hydroxysteroid dehydrogenase activity. During the first year of life, plasma F levels rose significantly (r(2) = 0,24;p = 0.01), and thereafter no further increase was seen until adulthood (r(2) = 0.01;p = 0.86). In contrast, plasma E significantly decreased during the first year of life (r(2) = -0.35;p < 0.001) and stayed unchanged thereafter (r(2) = 0.02;p = 0.81). As a consequence, the F/E ratio rose significantly during the first year (r(2) = 0.67;p < 0.001) but did not change afterward (r(2) = 0.001;p = 0.99). During the first year of Life, there is a change from the predominance of E, with low mineralocorticoid receptor affinity, to F, with high mineralocorticoid receptor affinity. This shift corresponds to the declining plasma concentrations of aldosterone during infancy. The changes may indicate a not yet recognized, significant change of 11 beta -hydroxysteroid dehydrogenase isoenzyme activity or alterations in the secretion of F and E, which may be of relevance for the development of arterial blood pressure in infancy.

关键词： 11-β-羟甾脱氢酶类年龄因素可的松/血液氢化可的松/血液羟甾类脱氢酶类/代谢受体盐皮质激素/代谢参考值青少年儿童儿童学龄前女(雌)性人类婴儿婴儿新生男(雄)性

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