Angiotensin II contributes to renal fibrosis independently of notch pathway activation
EntidadUAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
EditorPublic Library of Science
Fecha de edición2012-07-09
10.1371/journal.pone.0040490PLoS ONE 7.7 (2012): e40490
Financiado porThis 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.
ProyectoComunidad de Madrid. S2010/BMD-2321/FIBROTEAM
Versión del editorhttp://dx.doi.org/10.1371/journal.pone.0040490
MateriasEnzyme-linked immunoassays; Epithelial cells; Fibrosis; Gene expression; Kidneys; Notch signaling; Renal diseases; Renal system; Medicina
Derechos© 2012 Lavoz et al.
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.
Google Scholar:Lavoz, Carolina - Rodrigues Díez, Raquel - Benito-Martin, Alberto - Rayego-Mateos, Sandra - Rodrigues Díez, Raúl - Alique, Matilde - Ortiz Arduán, Alberto - Mezzano, Sergio - Egido, Jesús - Ruiz Ortega, Marta
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