title: Nuclear HSP90 regulates the glucocorticoid responsiveness of PBMCs in patients with idiopathic nephrotic syndrome.
abstract: Resistance to glucocorticoid (GC) is a challenge for the treatment of patients with idiopathic nephrotic syndrome (INS). Most of the effects of GC are mediated by the GC receptor (GR). Heat shock protein 90 (HSP90) is an important molecular chaperone for the GR and is supposed to be the key factor in regulating GC effects. In a previous study, we found that both the expression and nuclear distribution of HSP90 were increased in GC resistant INS patients. The aim of this study is to explore how these phenomena contribute to GC resistance in INS patients. Healthy subjects and INS patients with different GC responses were recruited. The total HSP90 expression was determined by reverse transcription-PCR and flow cytometric analysis. Western blot analysis was used to evaluate the expression of nuclear HSP90. Co-immunoprecipitation and electrophoretic mobility gel shift assays were performed to explore the interaction between HSP90 and the GR in the nucleus as well as the DNA-binding activity of GR. We induced the upregulation of the expression of total HSP90 in PBMCs by treatment with interleukin-6 in vitro and found that the nuclear HSP90 level, the DNA-binding activity of the GR and the cell apoptotic responsiveness to GC remained unchanged. Furthermore, an increased nuclear HSP90 was demonstrated mainly by binding to GR in the nucleus, while the DNA-binding activity of the GR dramatically decreased in GC resistant INS patients. The present results suggest that the accumulation of HSP90 in the nucleus potentially hinders DNA-binding activity and transactivation, which may contribute to GC resistance in patients with INS.
authors.affiliation: Department of Laboratory Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ouyang
authors.forename: Peisong
authors.initials: P
authors.lastname: Chen
authors.forename: Tang
authors.initials: T
authors.lastname: Jiang
authors.forename: Yili
authors.initials: Y
authors.lastname: Chen
authors.forename: Junxun
authors.initials: J
authors.lastname: Li
mesh_terms: D000328:Adult; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D004247:DNA