Abnormal expression and distribution of heat shock protein 90: potential etiologic immunoendocrine mechanism of glucocorticoid resistance in idiopathic nephrotic syndrome.
Resistance to glucocorticoid (GC) treatment in some patients with idiopathic nephrotic syndrome (INS) is a significant clinical problem. Heat shock protein 90 (HSP90) is the chaperon protein of the GC receptor, which is supposed to be the key factor of GC response. Therefore, we conducted this study to define the mechanisms of GC resistance related to HSP90. INS patients and cell lines with differing GC responses were included in the present study. We found that the level of HSP90 mRNA expression in INS patients was significantly higher than that in healthy controls and that HSP90 expression in GC-resistant INS patients was higher than that in GC-sensitive INS patients. A confocal immunofluorescence test was performed to investigate the subcellular localization of HSP90, and we found that the distribution of HSP90 in the GC-resistant INS group was greater in the nuclei than that of the GC-sensitive INS group. When the function of HSP90 was blocked by the HSP90-specific inhibitor, the GC sensitivity of GC-sensitive cells decreased remarkably. These results indicate that HSP90 plays a vital role in GC response. In addition, the abnormality in the mRNA level and subcellular distribution of HSP90 in GC-resistant INS patients may be etiologically significant in terms of endogenous/synthetic GC resistance. On one hand, it may disturb immunoendocrine regulation via endogenous GC and immune homeostasis and thus be involved in the occurrence of the immune-mediated disease; on the other hand, it may influence the patient's response to synthetic GC treatment and result in treatment failure.
Ouyang
Juan
J
Department of Laboratory Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshang Road II, Guangzhou, Guangdong, People's Republic of China. rfouyang@tom.com
Jiang
Tang
T
Tan
Min
M
Cui
Yinpeng
Y
Li
Xiaoyan
X
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D002460:Cell Line; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D011241:Prednisone / Q000008:administration & dosage* / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011241:Prednisone; C001277:geldanamycin