Nuclear HSP90 regulates the glucocorticoid responsiveness of PBMCs in patients with idiopathic nephrotic syndrome

Ouyang, Jian; Chen, Peisong; Tang, Jun‐Ming; Chen, Yili; Li, Junxun

doi:10.1016/j.intimp.2012.08.012

Cited by 20 publications

(17 citation statements)

References 29 publications

(32 reference statements)

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“…Recent evidence also indicates that the Hsp90 chaperone system facilitates passage into the nuclear pore [27]. Further, an increase in trafficking of Hsp90 into the nucleus has been shown to decrease GR binding activity to the glucocorticoid response element (GRE) and has been linked to glucocorticoid resistance [28]. Thus, we assessed the effects of PAE on Hsp90 levels in the cytosol (Figure 5D) and the nucleus (Figure S3 in File S1).…”

Section: Resultsmentioning

confidence: 99%

Prenatal Alcohol Exposure Modifies Glucocorticoid Receptor Subcellular Distribution in the Medial Prefrontal Cortex and Impairs Frontal Cortex-Dependent Learning

2014

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Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice.

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Section: Resultsmentioning

confidence: 99%

Prenatal Alcohol Exposure Modifies Glucocorticoid Receptor Subcellular Distribution in the Medial Prefrontal Cortex and Impairs Frontal Cortex-Dependent Learning

2014

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“…GR protein expression was measured by Western-blot as described before [8, 14]. An equal amount of protein (25 μ g/lane) from each cell lysate was separated on gel electrophoresis (sodium dodecyl sulfate-polyacrylamide electrophoresis) and electrophoretically transferred to polyvinylidenedifluoride membranes (Immobilon, Millipore, Billerica, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…GC and glucocorticoid receptor (GR) signaling play a critical role in regulating the immune system. Our previous studies indicated that autoimmunity is closely related with glucocorticoid resistance and GR dysfunction, which potentially serve as the mechanism of autoimmune disease [8, 9]. Taking these clues together, we hypothesize that prenatal GC exposure may contribute to the etiology of autoimmune disease through epigenetic modification of GR and glucocorticoid response [9].…”

Section: Introductionmentioning

confidence: 99%

Prenatal Dexamethasone Exposure Increases the Susceptibility to Autoimmunity in Offspring Rats by Epigenetic Programing of Glucocorticoid Receptor

Sun

Wan

Ouyang

et al. 2016

BioMed Research International

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Objective. Prenatal glucocorticoids (GC) can induce long term effects on offspring health. However, reports and related studies regarding the prolonged effects of prenatal GC on the development of autoimmunity are limited. Here, we aimed to explore the immunological effects of dexamethasone (DEX) exposure on young adults and whether glucocorticoid receptor (GR) is involved in this process. Methods. Wistar rats were given DEX during pregnancy. Susceptibility to autoimmunity in offspring was assessed using experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis (AIA) animal models. To reveal the possible mechanism, glucocorticoid response, GR expression, and methylation status were measured in peripheral blood mononuclear cells (PBMCs). Results. Our results showed that the DEX-treated rats had greater susceptibility to EAE (100% versus 62.5%, P < 0.05) and AIA (63.6% versus 0%, P < 0.05) than saline control group. Glucocorticoid response and GR expression were decreased in DEX rats. Significant difference was also found in the methylation levels of GR exon 1-10 to exon 1-11 region. Conclusions. Prenatal DEX administration increases the susceptibility to autoimmune diseases, which is potentially mediated by programming GR methylation status and glucocorticoid sensitivity.

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“…Mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) may result in steroid resistance. Also several polymorphisms were identified, which were linked to the disease (De Iudicibus et al, 2011;Mwinyi et al, 2010;Ouyang et al, 2012). In association with this, in recent years the term "Chrousos syndrome" appeared: a rare, familial or sporadic syndrome linked to mutation in the NR3C1 receptor gene, characterized by insensitivity to glucocorticoids due to reduced expression or absence of functional GR, and by elevated levels of adrenocorticotropic hormone (ACTH) (De Iudicibus et al, 2011).…”

Section: Genetic Factorsmentioning

confidence: 99%

“…Components of the GR heterocomplex were also examined, including heat shock proteins 90 (Hsp90), which act as important molecular chaperones for GR and are assumed to be of key importance for the control of glucocorticoid effects (Gross et al, 2009;Ouyang et al, 2012). Earlier studies demonstrated that both expression and nuclear distribution of Hsp90 were augmented in steroid-resistant patients with idiopathic nephrotic syndrome.…”

Section: Genetic Factorsmentioning

confidence: 99%

Molecular basis of mechanisms of steroid resistance in children with nephrotic syndrome.

Świerczewska

Ostalska‐Nowicka²,

Kempisty³

et al. 2013

Acta Biochim Pol

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Steroid therapy, due to a wide range of anti-inflammatory properties of steroids, is a basic field of treatment in many human diseases including the nephrotic syndrome in children. However, not all patients respond positively to therapy which divides them into steroid sensitive (SS) and steroid resistance (SR) individuals. Many potential factors associated with steroid resistance have been identified so far. It seems that genetic factors associated with glucocorticoid receptor α (GRα), the structure of heterocomplex of GR as well as glycoprotein P or cytochrome P450 may play a role in the induction of glucocorticoid resistance. Here we described several of the molecular mechanisms, which can regulate glucocorticoid sensitivity and resistance. Moreover, we presented genetic defects, which can lead to various effects of treatment and, in a longer perspective, enable clinicians to individualize therapies.

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Nuclear HSP90 regulates the glucocorticoid responsiveness of PBMCs in patients with idiopathic nephrotic syndrome

Cited by 20 publications

References 29 publications

Prenatal Alcohol Exposure Modifies Glucocorticoid Receptor Subcellular Distribution in the Medial Prefrontal Cortex and Impairs Frontal Cortex-Dependent Learning

Prenatal Alcohol Exposure Modifies Glucocorticoid Receptor Subcellular Distribution in the Medial Prefrontal Cortex and Impairs Frontal Cortex-Dependent Learning

Prenatal Dexamethasone Exposure Increases the Susceptibility to Autoimmunity in Offspring Rats by Epigenetic Programing of Glucocorticoid Receptor

Molecular basis of mechanisms of steroid resistance in children with nephrotic syndrome.

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