Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach

A Lautrette, S Li, R Alili, SW Sunnarborg, M Burtin… - Nature medicine, 2005 - nature.com
A Lautrette, S Li, R Alili, SW Sunnarborg, M Burtin, DC Lee, G Friedlander, F Terzi
Nature medicine, 2005nature.com
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-α (TGF-α) and its sheddase, TACE (also known as ADAM17) …
Abstract
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-α (TGF-α) 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-α or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-α 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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