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.

Conclusion: 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.