UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1

McCaffrey, JC; Webb, NJ; Poolman, TM; Fresquet, M; Moxey, C; Zeef, LAH; Donaldson, IJ; ... Lennon, R; + view all (2017) Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1. Scientific Reports , 7 , Article 6725. 10.1038/s41598-017-06810-y. Green open access

[thumbnail of Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1.pdf]
Preview
Text
Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1.pdf - Published Version

Download (5MB) | Preview

Abstract

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.

Type: Article
Title: Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-017-06810-y
Publisher version: http://dx.doi.org/10.1038/s41598-017-06810-y
Language: English
Additional information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: NEPHROTIC SYNDROME, MINERALOCORTICOID RECEPTOR, ACTIN CYTOSKELETON, GENE-EXPRESSION, TARGET, RHO, PHARMACOKINETICS, PREDNISOLONE, MECHANISMS, MUTATIONS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10103189
Downloads since deposit
38Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item