Corticosteroid-Binding Globulin is expressed in the adrenal gland and its absence impairs corticosterone synthesis and secretion in a sex-dependent manner

Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release

New roles for corticosteroid binding globulin and opposite expression profiles in lung and liver.

Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glu- cocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg -/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of gluco- corticoids in the lung. Lack of CBG does not modify the progression of inflammation associ- ated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11 β -HSD2, the enzyme involved in the deactivation of corticoste- rone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung

Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity.

Objective: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.Design: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 +/- 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI > 30 kg/m(2)).Methods: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritiumlabeled hormones.Results: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI > 40 kg/m(2)) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.Conclusions: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity

Presencia de corticosteroid-binding globulin (CBG) en tejidos extrahepáticos y alteraciones fisiológicas consecuencia de su déficit

[spa] Los glucocorticoides (GCs), un grupo de hormonas esteroides secretadas por la glándula suprarrenal, controlan el equilibrio entre movilización y deposición de reservas energéticas en el organismo y desempeñan papeles importantes durante las respuestas al estrés y la inflamación. La corticosteroid-binding globulin (CBG), transporta los GCs en la sangre y regula su disponibilidad, además de que diversas evidencias apuntan a un papel más activo en la modulación de la actividad glucocorticoide. La CBG se sintetiza principalmente en el hígado y es secretada a la circulación, siendo la síntesis hepática responsable de la concentración de CBG circulante. Sin embargo, también se ha descrito la síntesis de CBG en algunos tejidos periféricos con papel desconocido. La alteración de los niveles y la afinidad de la CBG por los CGs está asociada con dolor crónico, fatiga crónica, depresión, hipotensión y obesidad y con un eje hipotálamo-hipófisis-adrenal (HPA) alterado. El objetivo de esta tesis fue evaluar la expresión de CBG en tejidos extrahepáticos y determinar cómo su deficiencia afecta a diferentes procesos fisiológicos en los cuales los glucocorticoides presentan un papel relevante. Todos los estudios se han realizado utilizando ratones deficientes para CBG (KO) y sus correspondientes controles wild-type (WT). La colonia se estableció en el estabulario de la Facultad de Biología (UB) a partir de heterocigotos amablemente cedidos por el Dr. Thomas Willnow del Max-Delbrueck Center for Molecular Medicine de Berlín. Los resultados muestran que el tejido adiposo blanco sintetiza CBG aunque en una cantidad muy minoritaria respecto del hígado. Esta expresión es modulada al alza por una dieta hiperlipídica (HL) a pesar que los niveles de proteína no se ven aumentados, sugiriendo una regulación posttranscripcional o bien el flujo de CBG entre el tejido y el pool plasmático. Además, la dieta HL promueve el almacenamiento de lípidos en el tejido adiposo visceral en lugar del subcutáneo en los ratones KO para la CBG, intensifica en tejido adiposo epididimal la infiltración inicial de neutrófilos (1 semana) pero no la formación de crown-like structures ni los marcadores inflamatorios a largo plazo (12 semanas) acorde con la acción antiinflamatoria clásica de los glucocorticoides. Además, la resistencia a la insulina y el aumento de la lipólisis en adipocitos epididimales presentes ratifican que la deficiencia de CBG constituye un modelo de exceso moderado de glucocorticoides en el que actúan simultáneamente como antiinflamatorios y disruptores metabólicos. La CBG es necesaria para que se manifieste el dimorfismo sexual en los niveles de corticosterona total circulante, mayores en hembras que en machos. El pulmón presenta CBG con tinción específica en células epiteliales alveolares y macrófagos y su expresión presenta un dimorfismo sexual inverso al del hígado. Se describe que en la glándula adrenal existe síntesis de CBG, que se ubica principalmente en la médula adrenal a pesar que la síntesis de corticosterona se da en la corteza. En los ratones deficientes en CBG se observa una caída de la expresión del receptor de ACTH y de los enzimas claves implicados en la esteroidogénesis adrenal sobretodo en hembras. Finalmente, se ha confirmado la presencia de CBG en hipocampo de ratón. En el hipocampo, los ratones KO para la CBG presentaron mayores niveles de corticosterona libre, junto con un aumento de las respuestas mediadas por el MR, una mayor resistencia a la insulina y una mayor fosforilación de la proteína Tau. En conclusión, nuestros resultados indican que los ratones deficientes en CBG muestran una respuesta coherente con los efectos observados en situaciones de exceso de glucocorticoides.[eng] Glucocorticoids (GCs), a group of steroid hormones secreted by the adrenal gland, control the mobilization and deposition equilibrium of body nutrient stores, driving the responses to stress and inflammation. The corticosteroid-binding globulin (CBG) transports GCs in blood and regulates their availability. Some evidences point to a more active role of CBG in modulating GCs activity. CBG is synthesized mainly in liver and secreted to the blood. However, CBG expression have been detected in other tissues with an unknown role. Altered levels and GCs affinity in CBG are associated with chronic pain and fatigue, depression, hypotension and obesity. Our aim was to evaluate CBG expression in extrahepatic tissues and to assess if deficiency in CBG altered glucocorticoid action in physiological processes where GCs are important mediators. For this purpose, mice deficient in CBG (KO) or wild-type (WT) were used in all experiments. CBG is expressed in white adipose tissue where diet-induced obesity increases CBG mRNA but not protein levels, suggesting a post-transcriptional regulation or CBG secretion to the blood. Deficiency in CBG drives lipid partitioning from subcutaneous to visceral adipose depot under a context of lipid excess, promotes neutrophil infiltration in adipose tissue as an early-response to high fat diet without long-term changes and causes insulin resistance and adipocyte lipolysis. CBG is present in alveolar epithelial cells and macrophages in lung and its absence does not modify the progression of inflammation associated to pancreatitis, a pathology that disturbs lung functionality. In addition, CBG deficiency results in the loss of gender differences in corticosterone serum levels. CBG is synthesized in adrenal gland, being located in the medulla despite the corticosterone synthesis takes place in the cortex. Lack of CBG promotes the down-regulation of ACTH receptor and the main enzymes involved in corticosterone synthesis mainly in female KO mice. CBG is also expressed in the hippocampus where its absence elicits increased GCs levels and mineralocorticoid receptor mediated actions, as central insulin resistance and Tau phosphorylation. All together, these results indicate that deficiency in CBG is a model of sustained and moderate glucocorticoid excess that may act as a protector from excessive GCs action

Molecular Mechanisms of Diabetic Kidney Disease

The inflammatory component of diabetic kidney disease has become of great interest in recent years, with genetic and epigenetic variants playing a fundamental role in the initiation and progression of the disease. Cells of the innate immune system play a major role in the pathogenesis of diabetic kidney disease, with a lesser contribution from the adaptive immune cells. Other components such as the complement system also play a role, as well as specific cytokines and chemokines. The inflammatory component of diabetic kidney disease is of great interest and is an active research field, with the hope to find potential innovative therapeutic targets

New evidence in the treatment of diabetic kidney disease: what is finerenone’s contribution?

Contexto: la enfermedad renal diabética (ERD) es la primera causa a nivel mundial de enfermedad renal crónica (ERC) e impacta directamente en el riesgo cardiovascular y mortalidad de los pacientes con diabetes mellitus (DM). La finerenona, un antagonista selectivo del receptor mineralocorticoide (ARM), ha sido descrito en diversos estudios recientes como un fármaco que contribuye a la reducción de la progresión de la ERD y la disminución del riesgo cardiovascular, con un adecuado perfil de seguridad. Objetivo: realizar una revisión de la literatura sobre el impacto de la finerenona en la progresión del daño renal y el riesgo cardiovascular en los pacientes con ERD. Metodología: se realizó una búsqueda sistemática en diversas fuentes: PubMed (Medline, Biblioteca del Congreso de los Estados Unidos), Science Direct, Scopus, Embase y Lilacs; la búsqueda fue restringida a referencias en idioma español e inglés, sin límites en la fecha de publicación. Se utilizaron las siguientes palabras clave en el idioma inglés: diabetic renal disease, chronic kidney disease, diabetes mellitus, spironolactone, eplerenone, finerenone, mineralocorticoid receptor antagonist y sus correspondientes versiones en español. Resultados: Las referencias encontradas en la búsqueda fueron revisadas entre los diferentes autores para, posteriormente, proceder a realizar la elaboración del documento. Conclusiones: la finerenona es un medicamento que brinda cardio y nefroprotección en pacientes con ERD de fenotipo albuminúrico.Background: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) worldwide and has a direct impact on cardiovascular risk and mortality in patients with diabetes mellitus (DM). Finerenone, a selective mineralocorticoid receptor (MRA) antagonist, has been described in several recent studies as a drug that contributes to slowing the progression of CKD and reducing cardiovascular risk, with an adequate safety profile. Purpose: To carry out a review of the literature on the impact of finerenone on the progression of renal damage and cardiovascular risk in patients with DKD. Methodology: A systematic search were carried out in various sources: PubMed (Medline, United States Library of Congress), Science Direct, Scopus, Embase and Lilacs; the search was restricted to references in Spanish and English, with no limits on publication date. The following keywords in the English language were used: diabetic renal disease, chronic kidney disease, diabetes mellitus, spironolactone, eplerenone, finerenone, mineralocorticoid receptor antagonist and their corresponding Spanish versions.  Results: The references found in the search were reviewed among the different authors to subsequently proceed to prepare the document. Conclusions: Finerenone is a drug that provides cardio and nephroprotection in patients with DKD albuminuric phenotype.