TY - JOUR
T1 - Angiotensin II and EGF receptor cross-talk in chronic kidney diseases
T2 - A new therapeutic approach
AU - Lautrette, Alexandre
AU - Li, Shunqiang
AU - Alili, Rohia
AU - Sunnarborg, Susan W.
AU - Burtin, Martine
AU - Lee, David C.
AU - Friedlander, Gérard
AU - Terzi, Fabiola
N1 - Funding Information:
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.).
PY - 2005/8
Y1 - 2005/8
N2 - 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 Angll 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.
AB - 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 Angll 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.
UR - http://www.scopus.com/inward/record.url?scp=23844557144&partnerID=8YFLogxK
U2 - 10.1038/nm1275
DO - 10.1038/nm1275
M3 - Article
C2 - 16041383
AN - SCOPUS:23844557144
SN - 1078-8956
VL - 11
SP - 867
EP - 874
JO - Nature medicine
JF - Nature medicine
IS - 8
ER -