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.

• Authors: Vicente E Torres, William E Sweeney Jr, Xiaofang Wang, Qi Qian, Peter C Harris, Philip Frost, Ellis D Avner
• Journal: Kidney international (Kidney Int) Vol. 64 Issue 5 Pg. 1573-9 (Nov 2003) ISSN: 0085-2538 [Print] United States
• PMID: 14531789 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Quinazolines
• CL 387785
• ErbB Receptors

Topics

• Animals
• Disease Models, Animal
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Gastric Lavage
• Injections, Intraperitoneal
• Male
• Polycystic Kidney Diseases (drug therapy, prevention & control)
• Quinazolines (pharmacology)
• Rats
• Rats, Sprague-Dawley