Dose- and time-dependent glucocorticoid receptor signaling in podocytes.
Glucocorticoids (GC) are the primary therapy for idiopathic nephrotic syndrome (NS). Recent evidence has identified glomerular podocytes as a potential site of GC action in this disease. The objectives of this study were to determine the presence of key components of the glucocorticoid receptor (GR) complex and the functionality of this signaling pathway in podocytes and to explore potential opportunities for manipulation of GC responsiveness. Here, we show that cultured murine podocytes express key components of the GR complex, including the GR, heat shock protein 90, and the immunophilins FKBP51 and FKBP52. The functionality of GR-mediated signaling was verified by measuring several GC (dexamethasone)-induced responses, including 1) increases in mRNA and protein levels of selected GC-regulated genes (FKBP51, phenol sulfotransferase 1, αB-crystallin); 2) downregulation of the GR protein; 3) increased phosphorylation of the GR; and 4) translocation of the GR into the nuclear fraction. Dexamethasone-induced phosphorylation and downregulation of GR protein were also demonstrated in isolated rat glomeruli. Podocyte gene expression in response to dexamethasone was regulated at both the transcriptional and posttranscriptional levels, the latter also including protein degradation. Short-term, high-dose GC treatment resulted in similar changes in gene expression and GR phosphorylation to that of long-term, low-dose GC treatment, thus providing a molecular rationale for the known efficacy of pulse GC therapy in NS. Induction of FKBP51 and downregulation of the GR represent negative feedback mechanisms that can potentially be exploited to improve clinical GC efficacy. Collectively, these findings demonstrate the presence of key molecular components of the GR signaling pathway and its functionality in podocytes and identify novel opportunities for improving clinical GC efficacy in the treatment of NS.
Guess
Adam
A
Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, 700 Children's Dr., Columbus, OH 43205, USA.
Agrawal
Shipra
S
Wei
Chang-Ching
CC
Ransom
Richard F
RF
Benndorf
Rainer
R
Smoyer
William E
WE
D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone