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, HSP90, and the immunophilins FKBP51 and FKBP52. The functionality of GR-mediated signaling was verified by measuring several GC (dexamethasone)-induced responses, including: i) Increases in mRNA and protein levels of selected GC-regulated genes (FKBP51, phenol sulfotransferase 1, αB-crystallin), ii) Down-regulation of the GR protein, iii) Increased phosphorylation of the GR, and iv) Translocation of the GR into the nuclear fraction. Dexamethasone-induced phosphorylation and down-regulation of GR protein were also demonstrated in isolated rat glomeruli. Podocyte gene expression in response to dexamethasone was regulated at both the transcriptional and post-transcriptional 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 down-regulation of the GR represent negative feed-back 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.
- nephrotic syndrome
- glucocorticoid receptor
- Copyright © 2010, American Journal of Physiology - Renal Physiology