Abstract
Glucocorticoid receptor (GC), a founding member of the nuclear hormone receptor superfamily, is a glucocorticoid-activated transcription factor that regulates gene expression and controls the development and homeostasis of human podocytes. Synthetic glucocorticoids are the standard treatment regimens for proteinuria (protein in the urine) and nephrotic syndrome (NS) caused by kidney diseases. These include minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) or subsequent complications due to diabetes mellitus or HIV infection. However, unwanted side effects and steroid-resistance remain major issues for their long-term use. Furthermore, the mechanism by which glucocorticoids elicit their renoprotective activity in podocyte and glomeruli is poorly understood. Podocytes are highly differentiated epithelial cells that contribute to the integrity of kidney glomerular filtration barrier. Injury or loss of podocytes leads to proteinuria and nephrotic syndrome. Recent studies in multiple experimental models have begun to explore the mechanism of GC action in podocytes. This review will discuss progress in our understanding of the role of glucocorticoid receptor and glucocorticoids in podocyte physiology and their renoprotective activity in nephrotic syndrome.
Highlights
Glucocorticoid receptor (GR) is a founding member of the nuclear hormone receptor (NHRs) that control homeostasis, differentiation, proliferation and animal development
GRα is composed of four functional domains, the N-terminal ligand-independent transactivation domain (NTD) or activation function 1 (AF-1), the DNA-binding domain (DBD), the flexible hinge region and the ligand-binding domain (LBD)
Genome-wide analyses of GR-regulated genes and GR-binding sites in different cell types and tissues have recently been reported [30,31,32]. These experiments reveal the characteristics of genome-wide profiling of GR and genome-wide inventory of GR-binding sites. These results provide an exciting global view of the GR target genes and tissue-specific modes of GR action and potentially contribute to our understanding of glucocorticoid action
Summary
Glucocorticoid receptor (GR) is a founding member of the nuclear hormone receptor (NHRs) that control homeostasis, differentiation, proliferation and animal development. GR dissociates from the chaperone proteins and translocates into the nucleus, where it regulates transcription through multiple distinct modes of action (Figure 2) As a homodimer, it binds a cognate DNA sequence present in enhancers containing glucocorticoid response elements (GREs) to activate gene expression [7, 8]. In contrast to the dimer, ligand-bound GR monomeric is capable of transrepressing transcription through its interactions with other transcriptional regulators, such as nuclear factor kappa B (NF-κB) and activating protein-1 (AP-1) These interactions block co-activator recruitment and promote co-repressor recruitment, thereby altering chromatin structure and repressing target gene expression [18,19,20]. It has been proposed that Dex can directly act on the glomerular podocytes contributing to its therapeutic effects [29]
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