Journal Article

Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1

Donaldson, Ian J., Webb, Nicholas J., Zeef, Leo A. H., McCaffrey, James C., Lennon, Rachel, Moxey, Cressida, Poolman, Toryn M., Ray, David W., Fresquet, Maryline

2017

Overview

Nephrotic syndrome (NS) occurs when the glomerular filtration barrier becomes excessively permeable leading to massive proteinuria. In childhood NS, immune system dysregulation has been implicated and increasing evidence points to the central role of podocytes in the pathogenesis. Children with NS are typically treated with an empiric course of glucocorticoid (Gc) therapy; a class of steroids that are activating ligands for the glucocorticoid receptor (GR) transcription factor. Although Gc-therapy has been the cornerstone of NS management for decades, the mechanism of action, and target cell, remain poorly understood. We tested the hypothesis that Gc acts directly on the podocyte to produce clinically useful effects without involvement of the immune system. In human podocytes, we demonstrated that the basic GR-signalling mechanism is intact and that Gc induced an increase in podocyte barrier function. Defining the GR-cistrome identified Gc regulation of motility genes. These findings were functionally validated with live-cell imaging. We demonstrated that treatment with Gc reduced the activity of the pro-migratory small GTPase regulator Rac1. Furthermore, Rac1 inhibition had a direct, protective effect on podocyte barrier function. Our studies reveal a new mechanism for Gc action directly on the podocyte, with translational relevance to designing new selective synthetic Gc molecules.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/105 / 13/106 / 14/1 / 14/63 / 38 / 38/61 / 45 / 45/15 / 631/80/84/2341 / 692/4022/1585/2759/2758 / Antimetabolites, Antineoplastic - toxicity / Biological Transport - drug effects / Cell Line, Transformed / Cell Membrane - drug effects / Cell Movement - drug effects / Children / Electric Impedance / Gene Expression Profiling / Gene Expression Regulation / Gene regulation / Glucocorticoids / Glucocorticoids - pharmacology / Guanosine triphosphatases / Humanities and Social Sciences / Humans / Immune system / Microarray Analysis / Motility / multidisciplinary / Nephrotic syndrome / Podocytes - cytology / Podocytes - drug effects / Podocytes - metabolism / Prednisolone - pharmacology / Protective Agents - pharmacology / Proteinuria / Puromycin Aminonucleoside - antagonists & inhibitors / Puromycin Aminonucleoside - toxicity / rac1 GTP-Binding Protein - antagonists & inhibitors / rac1 GTP-Binding Protein - genetics / rac1 GTP-Binding Protein - metabolism / Rac1 protein / Receptors, Glucocorticoid - antagonists & inhibitors / Receptors, Glucocorticoid - genetics / Receptors, Glucocorticoid - metabolism / rhoA GTP-Binding Protein - genetics / rhoA GTP-Binding Protein - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Steroid hormones / Transcriptome