Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation | Zendy

Gisselle Carvajal | Zendy; Juan RodríguezVita | Zendy; Raquel RodriguesDíez | Zendy; Elsa SánchezLópez | Zendy; Mónica Rupérez | Zendy; Cecile Cartier | Zendy; Vanesa Esteban | Zendy; Alberto Ortíz | Zendy; Jesús Egido | Zendy; Sergio Mezzano | Zendy; Marta Ruiz–Ortega | Zendy

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Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation

Author(s) -

Gisselle Carvajal,

Juan RodríguezVita,

Raquel RodriguesDíez,

Elsa SánchezLópez,

Mónica Rupérez,

Cecile Cartier,

Vanesa Esteban,

Alberto Ortíz,

Jesús Egido,

Sergio Mezzano,

Marta Ruiz–Ortega

Publication year - 2008

Publication title -

kidney international

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 3.499

H-Index - 276

eISSN - 1523-1755

pISSN - 0085-2538

DOI - 10.1038/ki.2008.213

Subject(s) - transdifferentiation , angiotensin ii , smad , endocrinology , medicine , transforming growth factor beta , renin–angiotensin system , downregulation and upregulation , biology , fibrosis , chemistry , cancer research , transforming growth factor , microbiology and biotechnology , stem cell , biochemistry , gene , blood pressure

Epithelial to mesenchymal transdifferentiation is a novel mechanism that promotes renal fibrosis and here we investigated whether known causes of renal fibrosis (angiotensin II and transforming growth factor beta, TGFbeta) act through this pathway. We infused angiotensin II into rats for 1 day and found that it activated the Smad pathway which persisted for up to 2 weeks in chronically infused rats. Renal TGF-beta mRNA expression was increased at 3 days and its protein at 2 weeks suggesting Smad pathway activation occurred earlier than TGF-beta upregulation. In cultured human tubuloepithelial cells, angiotensin II caused a rapid activation of Smad signaling independent of TGF-beta however, Smad-dependent transcription after 1 day was TGF-beta mediated. Two weeks of angiotensin II infusion activated genes associated with epithelial mesenchymal transdifferentiation. Stimulation with angiotensin II for 3 days caused transdifferentiation of the cultured epithelial cells by TGF-beta-mediated processes; however, early changes were independent of endogenous TGF-beta. Smad7 overexpression, which blocks Smad2/3 activation, diminished angiotensin II-induced epithelial mesenchymal transdifferentiation. Our results show that angiotensin II activates the Smad signaling system by TGF-beta-independent processes, in vivo and in vitro, causing renal fibrosis.

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