title: Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition.
abstract: Hypertension is frequently associated with the development of renal vascular and glomerular fibrosis. The purpose of the present study was to investigate whether epidermal growth factor receptor (EGFR) activation participates in the development of renal fibrosis and to test if blockade of EGFR activation would have therapeutic effects. Experiments were performed during nitric oxide (NO) deficiency-induced hypertension in rats (L-NAME model). After 4 weeks of L-NAME treatment, animals developed hypertension associated to deterioration of renal structure and function. Over the same period, EGFR was activated twofold within glomeruli. This activation was accompanied by increased activity of the mitogen-activated protein kinase (MAPK) p42/p44 pathway and exaggerated collagen I expression. Gefitinib, an EGFR-tyrosine kinase inhibitor, given concomitantly with L-NAME, normalized MAPK activation and collagen I expression and prevented the decline of renal function and the development of fibrosis. Since endothelin mediates the L-NAME-induced fibrogenesis, the endothelin-EGFR interaction was tested in transgenic mice expressing luciferase under the control of collagen I-alpha2 promoter: In renal cortex of these animals, the endothelin-induced collagen I gene activity was inhibited by an EGFR-phosphorylation inhibitor. These results provide the first evidence that EGFR activation plays an important role in the progression of renal vascular and glomerular fibrosis.
authors.affiliation: INSERM U.489, Hôpital Tenon, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: François
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.forename: Dominique
authors.initials: D
authors.lastname: Chansel
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D024042:Collagen Type I; D003404:Creatinine / Q000097:blood; D019332:Endothelin-1 / Q000494:pharmacology / Q000633:toxicity; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005355:Fibrosis; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000517:prevention & control; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D007511:Ischemia / Q000139:chemically induced / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009336:Necrosis; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000172:deficiency*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced / Q000517:prevention & control; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D024042:Collagen Type I; D019332:Endothelin-1; D011799:Quinazolines; D009569:Nitric Oxide; D003094:Collagen; D003404:Creatinine; D066246:ErbB Receptors; D000077156:Gefitinib; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline; D019331:NG-Nitroarginine Methyl Ester