EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats.
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.
Torres
Vicente E
VE
Division of Nephrology, Mayo Foundation, Rochester, Minnesota 55905, USA. torres.vincent@mayo.edu
Sweeney
William E
WE
Wang
Xiaofang
X
Qian
Qi
Q
Harris
Peter C
PC
Frost
Philip
P
Avner
Ellis D
ED
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
D011799:Quinazolines; C118029:CL 387785; D066246:ErbB Receptors