Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach.
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.
Lautrette
Alexandre
A
INSERM U426, Hôpital Necker Enfants Malades, IFR 94, Université Paris 5, 149 Rue de Sèvres, 75015 Paris, France.
Li
Shunqiang
S
Alili
Rohia
R
Sunnarborg
Susan W
SW
Burtin
Martine
M
Lee
David C
DC
Friedlander
Gérard
G
Terzi
Fabiola
F
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000628:therapy*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017931:DNA Primers; D006877:Hydroxamic Acids; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C442468:WTACE2 compound; D000804:Angiotensin II; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D019808:Losartan