[Angiotensin and EGF receptor cross-talk in chronic kidney diseases: towards a new therapeutic approach].
Angiotensin plays a major role in renal deterioration, and inhibition of the renin-angiotensin system slows the progression of renal lesions after nephron reduction both in animal models and in humans with chronic kidney diseases. The EGF receptor (EGFR) has recently been recognized as a key molecule in the progression of chronic renal failure, but the interaction between angiotensin and EGF is poorly understood. We show that transgenic mice harboring a dominant negative form of EGFR are resistant to the progression of renal lesions induced by nephron reduction or angiotensin infusion. TGF-alpha, an EGFR ligand, and its sheddase TACE, are overexpressed after angiotensin infusion, and angiotensin-induced renal lesions are blunted in TGF-alpha knockout mice and by pharmacological TACE blockade. After nephron reduction, angiotensin-converting-enzyme inhibitors and angiotensin receptor antagonists prevent TGF-alpha and TACE accumulation. These results indicate that EGFR transactivation by angiotensin plays a crucial role in renal deterioration and that pharmacological inhibitors of TACE might be useful for preventing the progression of chronic kidney diseases.
Friedlander
Gérard
G
Inserm, U811, Paris F-75015, France.
Terzi
Fabiola
F
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000809:Angiotensins / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D020239:Receptor Cross-Talk
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D000804:Angiotensin II; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse