The Role of Glucocorticoid Receptors in Podocytes and Nephrotic Syndrome

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.

Keywords: Glucocorticoid receptor; Nephrotic syndrome; Podocyte; focal segmental glomerulosclerosis.

Figure 1. The GR family proteins

Human GR harbors three functional domains: N-terminal domain (NTD), middle DNA-binding domain (DBD) and the C-terminal ligand-binding domain (LBD). The DBD and LBD are linked by the hinge region (HR). Alternative splicing of the NR3C1 (gene encoding GR) gene generates the isoforms GRα, GRβ, GRγ, GR-A, and GR-P, which differ in size and sequence of HR and/or LBD.

Figure 2. Molecular mechanism of GR signaling pathways

Glucocorticoids diffuse across the cell membrane to the cytosol, where they bind GR. Glucocorticoid binding promotes dissociation of GR from chaperone proteins (HSPs) and subsequent nuclear translocation. Once in the nucleus, GR forms hetero- or homodimers and interacts with DNA to control gene transcription. Ligand-bound GR can lead to either activation or repression of gene transcription. TF: transcription factor; GRE, glucocorticoid response element; nGRE, negative glucocorticoid response element; TFRE: transcription factor response element.

Figure 3. A diagram showing the structure and components of the renal glomerular filtration system, from the kidney to podocyte

The glomerular filtration barrier consists of fenestrated endothelial cells, glomerular base membrane, and podocytes.

Figure 4. A schematic diagram depicting components of the podocyte slit diaphragm and foot processes and slit diaphragm proteins

Proteins that make up the SD between adjacent foot processes are depicted. Nephrin, NEPH1, NEPH2, P-cadherin, and FAT are membrane-spanning proteins that have large extracellular domains that are important for signaling events that determine the structural integrity of podocyte foot processes. These proteins include the slit diaphragm interact with intracellular adapter proteins, including CD2-AP, ZO-1, Synaptopodin, and ACTN4. The adapter proteins bind to filamentous actin (F-actin). The adhesion molecules dystroglycan and α3β1 integrin anchor the podocyte to the underlying glomerular basement membrane (GBM).

Figure 5. The mechanism of the podocyte injury and the protective effected by glucocorticoids

Several causes are known to contribute to podocyte injury. After the injury, podocytes can undergo cytoskeleton derangement, effacement, detachment or apoptosis. The mechanisms by which glucocorticoids exerts its renoprotective effect involve several mechanisms that protect podocyte from injury.