Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1

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...

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Autores principales:	James C. McCaffrey, Nicholas J. Webb, Toryn M. Poolman, Maryline Fresquet, Cressida Moxey, Leo A. H. Zeef, Ian J. Donaldson, David W. Ray, Rachel Lennon
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/964db73076a04303b20e5d2795d70cae
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spelling	oai:doaj.org-article:964db73076a04303b20e5d2795d70cae2021-12-02T16:06:07ZGlucocorticoid therapy regulates podocyte motility by inhibition of Rac110.1038/s41598-017-06810-y2045-2322https://doaj.org/article/964db73076a04303b20e5d2795d70cae2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06810-yhttps://doaj.org/toc/2045-2322Abstract 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.James C. McCaffreyNicholas J. WebbToryn M. PoolmanMaryline FresquetCressida MoxeyLeo A. H. ZeefIan J. DonaldsonDavid W. RayRachel LennonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James C. McCaffrey Nicholas J. Webb Toryn M. Poolman Maryline Fresquet Cressida Moxey Leo A. H. Zeef Ian J. Donaldson David W. Ray Rachel Lennon Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
description	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.
format	article
author	James C. McCaffrey Nicholas J. Webb Toryn M. Poolman Maryline Fresquet Cressida Moxey Leo A. H. Zeef Ian J. Donaldson David W. Ray Rachel Lennon
author_facet	James C. McCaffrey Nicholas J. Webb Toryn M. Poolman Maryline Fresquet Cressida Moxey Leo A. H. Zeef Ian J. Donaldson David W. Ray Rachel Lennon
author_sort	James C. McCaffrey
title	Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
title_short	Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
title_full	Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
title_fullStr	Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
title_full_unstemmed	Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1
title_sort	glucocorticoid therapy regulates podocyte motility by inhibition of rac1
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/964db73076a04303b20e5d2795d70cae
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Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1

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