Nature Medicine
11, 867 - 874 (2005)
Published online: 24 July 2005; | doi:10.1038/nm1275
Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approachAlexandre Lautrette1, Shunqiang Li2, Rohia Alili1, Susan W Sunnarborg2, Martine Burtin1, David C Lee2, Gérard Friedlander1
& Fabiola Terzi11
INSERM U426, Hôpital Necker Enfants Malades, IFR 94, Université Paris 5, 149 Rue de Sèvres, 75015
Paris, France. 2
Department of Biochemistry & Biophysics, 405 Mary Ellen Jones Building UNC School of Medicine, Chapel Hill, North Carolina, 27599-7260, USA.
Correspondence should be addressed to Fabiola Terzi terzi@necker.fr Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor- (TGF-) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF- or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF- and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.
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