Corticoids synergize with IL-1 in the induction of LCN2.

OBJECTIVE: Lipocalin-2 (LCN2) is an adipokine that was first identified in neutrophil granules. In the last years it was recognized as a factor that could impair chondrocyte phenotype, cartilage homeostasis as well as growth plate development. Both pro-inflammatory cytokines and glucocorticoids (GCs) modulate LCN2 expression. Actually, GCs were found to be LCN2 inducers, suggesting that part of the negative actions exerted by these anti-inflammatory drugs at cartilage level could be mediated by this adipokine. So, in this study we wanted to investigate whether corticoids were able to act in synergy with IL-1 in the induction of LCN2 and the signaling pathway involved in this process. MATERIALS AND METHODS: For the realization of this work, ATDC5 mouse chondrogenic cell line was used. We determined the mRNA and protein expression of LCN2 by real-time reverse transcription-polymerase chain reaction (RT-qPCR) and western blot respectively, after GC or mineralcorticoid treatment. Different signaling pathways inhibitors were also used. RESULTS: GC and mineralcorticoid were able to induce the expression of LCN2 in ATDC5 cells. Interestingly, both corticoids synergized with IL-1 in the induction of LCN2. The effect of these corticoids on the expression of LCN2 occurred through GC or mineralcorticoid receptors and the kinases PI3K, ERK1/2 and JAK2. CONCLUSIONS: Prolonged use of corticoids may have detrimental effects on cartilage homeostasis. Based on our results, we conclude that corticoids could increase the negative actions exerted by IL-1 by increasing the expression of LCN2.

[Cardiac arrest with syndrome of apparent mineralocorticoid excess].

Ventricular fibrillation is an unknown complication to the syndrome of apparent mineralocorticoid excess (SAME). This case report describes a young woman admitted with hypo-kalaemia and hypertension. Concentrations of both P-renin and P-aldosterone were low and urinary steroid metabolites revealed an abnormal excretion pattern pointing to the diagnosis of SAME. Three years later the woman suffered from ventricular fibrillation due to the hypokalaemia caused by her disease. This case report demonstrates the need for increased attention on the potassium concentration in patients with SAME.

Papel de la quinasa regulada por suero y glucocorticoides 1 en las alteraciones cardiacas producidas por la aldosterona en ratas / Role of serum and glucocorticoid regulated kinase 1 in cardiac alterations induced by aldosterone in rats

Introducción: La aldosterona contribuye al desarrollo de la hipertrofia cardiaca. La quinasa regulada por suero y glucocorticoides 1 (SGK-1) desempeña un papel central en el mecanismo de acción de la aldosterona. Objetivo Analizar las alteraciones cardiacas estructurales, funcionales, inflamatorias y oxidativas, así como la expresión del SGK-1, producidas por la administración de aldosterona+sal en ratas. Material y métodos Se utilizaron ratas macho Wistar (250g). Un grupo de animales recibió una dosis diaria de aldosterona 1mg/kg/día subcutánea (s.c.)+NaCl al 1% en el agua de bebida. Otro grupo de animales con hiperaldosteronismo inducido fue tratado con un antagonista de los receptores de mineralocorticoides, la espironolactona (200mg/kg/día, s.c.). Como controles se utilizaron animales a los que se les administró el vehículo (s.c.) y animales a los que se les administró espironolactona (200mg/kg/día, s.c.). El periodo de evolución fue de 21días. Se tomaron las siguientes medidas hemodinámicas: PAS, PAD, FC, pDfVI, PSVI, dP/dt+ y dP/dt-. Como índice de hipertrofia cardiaca se calculó el peso relativo del corazón. Se valoró (..) (AU)

Introduction: Aldosterone induces cardiac hypertrophy and it is known to induce serum and glucocorticoid regulated kinase 1 (SGK-1) gene expression. Aim: We aimed to evaluate structural, functional, inflammatory and oxidative alterations, aswell as serum and glucocorticoid regulated kinase1 (SGK-1) expression, produced in rat heartby aldosterone + salt administration. Treatment with spironolactone was evaluated to prove mineralocorticoids mediation. Matherial and methods: Male Wistar rats received aldosterone (1 mg/kg/day) + 1% NaCl for3 weeks. Half of the animals were treated with spironolactone (200 mg/kg/day). At the end of treatment hemodynamics were measured: SBP, DBP, LVEDP, LVSP, +dP/dt and ---dP/dt. Heartrelative weight was measured as cardiac hypertrophy index. mRNA expression of TGF- , CTGF,MMP2, TIMP2, TNF- ,IL-1 , p22phox, eNOS and SGK-1 were measured. Cardiac collagen content was measured by histological techniques. Results: SBP and DBP, LVSP and LVEDP were elevated (P < .05) in aldosterone + salt-treatedrats. ---dP/dt decreased (P < .05) in aldosterone + salt-treated rats, but +dP/dt was similar in all groups. Spironolactone normalized (P < .05) SBP, DBP, LVSP, LVEDP and ---dP/dt. Relative heart weight, collagen content, mRNA expression of TGF- , CTGF, MMP2, TIMP2, TNF- , IL-1 , p22phox, eNOS and SGK-1 were increased (P < .05) in aldosterone + salt-treated rats, being reduced by spironolactone (P < .05).Conlusions: SGK-1 might be a key mediator in the structural, functional and molecular cardiacalterations induced by aldosterone + salt in rats. All the observed changes and mediators are related with activation of mineralocorticoid receptors (AU)

Pharmacodynamics and pharmacokinetics of synthetic mineralocorticoids and glucocorticoids: receptor transactivation and prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases.

Glucocorticoid (GC) and mineralocorticoid (MC) action in target tissues is determined by prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases (HSDs) and receptor transactivation. We characterized these parameters for steroids often used in clinical practice. HSD activity was examined in human liver (HSD1) and kidney microsomes (HSD2) and in CHO cells stably transfected with both enzymes. GC and MC transcriptional activity was tested by luciferase assay in CV-1 cells transfected with human GC or MC receptor expression vectors. The 11-hydroxy-group is necessary for GC and MC receptor transactivation. As HSD2 oxidizes 11-hydroxysteroids to inactive 11-dehydrosteroids, GC and MC activity in HSD2-expressing tissues (kidney, colon) is regulated by this enzyme. As 9alpha-fluorination (such as in 9alpha-fluorocortisol) decreases oxidation by HSD2 and increases both GC and MC receptor transactivation, this modification leads to optimal, but non-selective transactivation of both receptors. Increased GC receptor and decreased MC receptor transactivation leading to more selective GC activity is reached using the following substituents: 16beta-methyl (in betamethasone), 16alpha-methyl (in dexamethasone) and triangle up 1-dehydro-configuration (in prednisolone). Whereas the modifications in position 16 decrease oxidation by HSD2, the triangle up 1-dehydro-configuration increases HSD2-activity leading to an enhanced inactivation of prednisolone compared to all other steroids. 9alpha-fluorocortisol, the most frequently used substance for MC-substitution, seems to be the best choice of available steroids for this purpose. Whereas GC selectivity can be improved by hydrophobic substituents in position 16 and the triangle up 1-dehydro-configuration, maximal GC activity needs additional fluorination in position 9alpha (such as in dexamethasone). For GC therapy directed to HSD2-expressing organs, widely used prednisolone does not seem to be the optimal recommendation.

Binding and action of glucocorticoids and mineralocorticoids in rabbit mammary gland. Exclusive participation of glucocorticoid type II receptors for stimulation of casein synthesis.

In order to ascertain whether the effect of corticoids upon casein synthesis in pregnant rabbit mammary gland culture is due to interactions with classical glucocorticoid or type I (mineralocorticoid) receptors we have demonstrated the existence of both types of receptors in the tissue and have studied the effects of aldosterone and the specific glucocorticoid agonist RU 28362 upon casein synthesis in tissue culture. Both compounds significantly stimulated prolactin-induced casein synthesis. On dose-response studies RU 28362 proved to be as active as dexamethasone, cortisol was active at intermediate concentrations and aldosterone was the least active. The three glucocorticoids were able to stimulate DNA synthesis in the tissue, but aldosterone had no effect. Finally, RU 486, a potent glucocorticoid antagonist, blocked the action of aldosterone and the other corticoids upon casein synthesis, whereas spironolactone, a mineralocorticoid antagonist, was unable to do so. These results demonstrate that the stimulatory effect of corticoids upon casein synthesis in pregnant rabbit mammary tissue culture is mediated through classical (type II) glucocorticoid receptors. Transferrin accumulation in the tissue was not modified by any treatment, indicating that the action of the steroids was specific for casein, and not a general stimulation of protein synthesis.