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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 approach

Alexandre Lautrette1, Shunqiang Li2, Rohia Alili1, Susan W Sunnarborg2, Martine Burtin1, David C Lee2, Gérard Friedlander1 & Fabiola Terzi1

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-alpha (TGF-alpha) 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-alpha or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-alpha 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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