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

Nature Medicine volume 11, pages 867–874 (2005)Cite this article

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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Figure 1: Overexpression of a dominant negative isoform of EGFR prevents lesion development in AngII-treated mice.
Figure 2: AngII stimulates TGF-α shedding and MAP kinase phosphorylation in GN5 cells.
Figure 3: TGF-α is increased and essential for AngII-induced renal damage.
Figure 4: TACE activation is crucial for AngII-induced TGF-α overexpression in lesion development.
Figure 5: AngII-induced EGFR phosphorylation is abolished by EGFR, TGF-α or TACE inhibition in mice.
Figure 6: Inhibition of AngII signaling pathway attenuates development of lesions and abrogates overexpression of TGF-α and TACE after nephron reduction.

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Acknowledgements

We are grateful to S. Le Corre, M. Muffat-Joly and Y. Xiong. We thank W. Russell and M. Stevenson for TGF-α RIA measurements and E. Esquivel, M. Pontoglio and D. Laouari for critical advice. We are grateful to Wyeth-Ayerst Research Laboratories and MSD Laboratories for WTACE2 and losartan, respectively. This work was supported by INSERM, Université René Descartes, Laboratoires de Recherches Physiologiques and Centre de Recherche Industrielle et Technique and by US National Institutes of Health/National Cancer Institute grants CA43793 and CA85410 (to D.C.L.).

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Authors and Affiliations

  1. INSERM U426, Hôpital Necker Enfants Malades, IFR 94, Université Paris 5, 149 Rue de Sèvres, Paris, 75015, France

    Alexandre Lautrette, Rohia Alili, Martine Burtin, Gérard Friedlander & Fabiola Terzi

  2. Department of Biochemistry & Biophysics, 405 Mary Ellen Jones Building UNC School of Medicine, Chapel Hill, 27599-7260, North Carolina, USA

    Shunqiang Li, Susan W Sunnarborg & David C Lee

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  1. Alexandre Lautrette
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Correspondence to Fabiola Terzi.

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Lautrette, A., Li, S., Alili, R. et al. Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nat Med 11, 867–874 (2005). https://doi.org/10.1038/nm1275

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