title: EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats.
abstract: BACKGROUND
  Increasing evidence supports an important role for the epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha)/EGF receptor (EGFR) axis in promoting tubular epithelial cell proliferation and cyst formation in polycystic kidney disease (PKD).
  
  
  METHODS
  To determine whether the inhibition of EGFR tyrosine kinase activity can attenuate the development of PKD in the Han:SPRD rat, a frequently used animal model of autosomal-dominant slowly progressive PKD (ADPKD), wild-type and cy/+ rats were treated with EKI-785 or EKB-569 or with vehicle alone. Western analysis, immunoprecipitation, and immunohistochemistry were used to ascertain the expression, activation, and localization of EGFR.
  
  
  RESULTS
  Overexpression, activation and apical mislocalization of EGFR were observed in the cy/+ rats. The intraperitoneal administration of EKI-785 reversed the activation of the EGFR to the level observed in wild-type animals. The intraperitoneal administration of EKI-785 (90 mg/kg body weight every third day) or of EKB-569 (20 mg/kg body weight every third day) to cy/+ rats resulted in lower kidney weights, serum concentrations of blood urea nitrogen (BUN), cyst volumes, and fibrosis scores. The administration of EKB-569 by gavage was less effective probably because of lower bioavailability.
  
  
  CONCLUSIONS
  These results support a significant role for the EGF/TGF-alpha/EGFR axis in the development of PKD in the Han:SPRD rat and the therapeutic potential of EGFR tyrosine kinase inhibition in ADPKD.
authors.affiliation: Division of Nephrology, Mayo Foundation, Rochester, Minnesota 55905, USA. torres.vincent@mayo.edu
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: William E
authors.initials: WE
authors.lastname: Sweeney
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Qian
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.forename: Philip
authors.initials: P
authors.lastname: Frost
authors.forename: Ellis D
authors.initials: ED
authors.lastname: Avner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005751:Gastric Lavage; D007274:Injections, Intraperitoneal; D008297:Male; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000517:prevention & control*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011799:Quinazolines; C118029:CL 387785; D066246:ErbB Receptors