Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.

Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kina...

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Autores principales:	Andrea Babelova, Felix Jansen, Kerstin Sander, Matthias Löhn, Liliana Schäfer, Christian Fork, Hartmut Ruetten, Oliver Plettenburg, Holger Stark, Christoph Daniel, Kerstin Amann, Hermann Pavenstädt, Oliver Jung, Ralf P Brandes
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a03051003e6a4e74ada3d1db6d87b6ce
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spelling	oai:doaj.org-article:a03051003e6a4e74ada3d1db6d87b6ce2021-11-18T08:47:50ZActivation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.1932-620310.1371/journal.pone.0080328https://doaj.org/article/a03051003e6a4e74ada3d1db6d87b6ce2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24244677/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.Andrea BabelovaFelix JansenKerstin SanderMatthias LöhnLiliana SchäferChristian ForkHartmut RuettenOliver PlettenburgHolger StarkChristoph DanielKerstin AmannHermann PavenstädtOliver JungRalf P BrandesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e80328 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrea Babelova Felix Jansen Kerstin Sander Matthias Löhn Liliana Schäfer Christian Fork Hartmut Ruetten Oliver Plettenburg Holger Stark Christoph Daniel Kerstin Amann Hermann Pavenstädt Oliver Jung Ralf P Brandes Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
description	Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.
format	article
author	Andrea Babelova Felix Jansen Kerstin Sander Matthias Löhn Liliana Schäfer Christian Fork Hartmut Ruetten Oliver Plettenburg Holger Stark Christoph Daniel Kerstin Amann Hermann Pavenstädt Oliver Jung Ralf P Brandes
author_facet	Andrea Babelova Felix Jansen Kerstin Sander Matthias Löhn Liliana Schäfer Christian Fork Hartmut Ruetten Oliver Plettenburg Holger Stark Christoph Daniel Kerstin Amann Hermann Pavenstädt Oliver Jung Ralf P Brandes
author_sort	Andrea Babelova
title	Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
title_short	Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
title_full	Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
title_fullStr	Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
title_full_unstemmed	Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
title_sort	activation of rac-1 and rhoa contributes to podocyte injury in chronic kidney disease.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a03051003e6a4e74ada3d1db6d87b6ce
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Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.

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