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Pharmacological Modulation of Epithelial Mesenchymal Transition Caused by Angiotensin II. Role of ROCK and MAPK Pathways

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Abstract

Purpose

Tubulointerstitial fibrosis is a final common pathway to end-stage chronic kidney diseases, which are characterized by elevated renal angiotensin II (AngII) production. This peptide participates in kidney damage inducing fibrosis and epithelial mesenchymal transition (EMT). Our aim was to describe potential therapeutic targets in AngII-induced EMT, investigating the blockade of different intracellular pathways.

Methods

Studies were done in human tubular epithelial cells (HK2 cell line), evaluating changes in phenotype and EMT markers (Western blot and immunofluorescence).

Results

Treatment of HK2 cells with AngII for 3 days caused transdifferentiation into myofibroblast-like cells. The blockade of MAPKs cascade, using specific inhibitors of p38 (SB203580), extracellular signal-regulated kinase1/2 (ERK; PD98059) and Jun N-terminal kinase (JNK) (SP600125), diminished AngII-induced EMT. The blockade of RhoA/ROCK pathway, by transfection of a RhoA dominant-negative vector or by ROCK inhibition with Y-27632 or fasudil, inhibited EMT caused by AngII. Connective tissue growth factor (CTGF) is a downstream mediator of AngII-induced EMT. MAPKs and ROCK inhibitors blocked CTGF overexpression induced by AngII. HMG-CoA reductase inhibitors, although blocked AngII-mediated kinases activation, only partially diminished EMT and did not regulate CTGF.

Conclusions

These data suggest a potential therapeutic use of kinase inhibitors in renal fibrosis.

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Abbreviations

AngII:

angiotensin II

AT:

angiotensin receptors

CTGF:

connective tissue growth factor

EMT:

epithelial mesenchymal transition

ERK:

extracellular signal-regulated kinase1/2

FBS:

fetal bovine serum

HK2:

human tubular epithelial cell line

HMG-CoA reductase:

3-hydroxy-3-methylglutaryl coenzyme A reductase

JNK:

Jun N-terminal

MAPK:

mitogen activated kinases

ROCK:

rho-kinase

TGF-β:

transforming growth factor-beta

VSMC:

vascular smooth muscle cells

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Acknowledgment

This work has been supported by grants from SAF 2005-03378 of the Ministerio de Educación y Ciencia, Sociedad Española de Nefrologia, Red temática de Investigación Renal, REDINREN (ISCIII-RETIC RD06/0016/0004) from the Instituto de Salud Carlos III from Ministerio de Sanidad y Consumo, EU project (DIALOK, LSHB-CT-2007-036644), PCI Iberoamerica and FONDECYT, Chile (1080083). E.S-L, J. R-V. are fellows of FIS. G.C. is a fellow of Fundación Carolina and Fundación Iñigo Alvarez de Toledo. We want to thank Ma Mar Gonzalez Garcia-Parreño and Sandra López León for their technical help. There is no conflict of interest.

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Authors and Affiliations

  1. Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain

    Raquel Rodrigues-Díez, Elsa Sánchez-López, Juan Rodríguez-Vita, Raúl Rodrigues Díez & Marta Ruiz-Ortega

  2. Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile

    Gisselle Carvajal-González & Sergio Mezzano

  3. Servicio de Nefrología, Hospital Universitario La Paz, Madrid, Spain

    Rafael Selgas

  4. Nephrology Department, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040, Madrid, Spain

    Alberto Ortiz & Jesús Egido

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  3. Elsa Sánchez-López
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Corresponding author

Correspondence to Marta Ruiz-Ortega.

Additional information

Raquel Rodrigues-Díez and Gisselle Carvajal-González contributed equally to this paper.

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Rodrigues-Díez, R., Carvajal-González, G., Sánchez-López, E. et al. Pharmacological Modulation of Epithelial Mesenchymal Transition Caused by Angiotensin II. Role of ROCK and MAPK Pathways. Pharm Res 25, 2447–2461 (2008). https://doi.org/10.1007/s11095-008-9636-x

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  • DOI: https://doi.org/10.1007/s11095-008-9636-x

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