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

Nat Med. 2005 Aug;11(8):867-74. doi: 10.1038/nm1275. Epub 2005 Jul 24.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Angiotensin II / antagonists & inhibitors
  • Angiotensin II / metabolism*
  • Angiotensin II / toxicity
  • Animals
  • Blotting, Western
  • DNA Primers
  • ErbB Receptors / metabolism*
  • Fluorescent Antibody Technique
  • Hydroxamic Acids / pharmacology
  • Immunohistochemistry
  • Kidney / pathology
  • Kidney / physiology
  • Kidney Diseases / chemically induced
  • Kidney Diseases / metabolism*
  • Kidney Diseases / therapy*
  • Losartan / pharmacology
  • Mice
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism


  • DNA Primers
  • Hydroxamic Acids
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • WTACE2 compound
  • Angiotensin II
  • ErbB Receptors
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse
  • Losartan