Angiotensin II contributes to renal fibrosis independently of notch pathway activation
Entity
UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)Publisher
Public Library of ScienceDate
2012-07-09Citation
10.1371/journal.pone.0040490
PLoS ONE 7.7 (2012): e40490
ISSN
1932-6203 (online)DOI
10.1371/journal.pone.0040490Funded by
This work was supported by grants from the Instituto de Salud Carlos III (PI081564, PI11/01854 and PS09/00447 and REDINREN ISCIII-RETIC RD06/0016/0004), Sociedad Española de Nefrología, Comunidad de Madrid (S2010/BMD-2321), Agencia Española de Cooperación Internacional (PCI Iberoamerica; A/9571/07), Fundación Lilly, FONDECYT Chile 1080083 and 1120480. CL and RRD are fellows of ISCIII. Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO.Project
Comunidad de Madrid. S2010/BMD-2321/FIBROTEAMEditor's Version
http://dx.doi.org/10.1371/journal.pone.0040490Subjects
Enzyme-linked immunoassays; Epithelial cells; Fibrosis; Gene expression; Kidneys; Notch signaling; Renal diseases; Renal system; MedicinaRights
© 2012 Lavoz et al.Abstract
Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II
(AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of
profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In
cultured human tubular epithelial cells the Notch activation by transforming growth factor-b1 (TGF-b1) has been involved in
epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-b1. For these reasons, our aim was to
investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced
responses. In cultured human tubular epithelial cells, TGF-b1, but not AngII, increased the Notch pathway-related gene
expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts,
AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify
AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic
infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated
Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not
modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly
indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings
showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to
understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.
Files in this item
Google Scholar:Lavoz, Carolina
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Rodrigues Díez, Raquel
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Benito-Martin, Alberto
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Rayego-Mateos, Sandra
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Rodrigues Díez, Raúl
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Alique, Matilde
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Ortiz Arduán, Alberto
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Mezzano, Sergio
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Egido, Jesús
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Ruiz Ortega, Marta
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