EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han: SPRD rats

Vicente Torres, William E. Sweeney, Xiaofang Wang, Qi Qian, Peter C Harris, Philip Frost, Ellis D. Avner

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Background. Increasing evidence supports an important role for the epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-a)/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-α/EGFR axis in the development of PKD in the Han:SPRD rat and the therapeutic potential of EGFR tyrosine kinase inhibition in ADPKD.

Original languageEnglish (US)
Pages (from-to)1573-1579
Number of pages7
JournalKidney International
Volume64
Issue number5
DOIs
StatePublished - Nov 2003

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Polycystic Kidney Diseases
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Epidermal Growth Factor
Cysts
Body Weight
Transforming Growth Factor alpha
Wild Animals
Blood Urea Nitrogen
Immunoprecipitation
Biological Availability
Fibrosis
Animal Models
Epithelial Cells
Immunohistochemistry
Cell Proliferation
Kidney
Weights and Measures
Serum

Keywords

  • EGF receptor
  • EKB-569
  • EKI-785
  • HanSPRD rat
  • Polycystic kidney disease

ASJC Scopus subject areas

  • Nephrology

Cite this

EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han : SPRD rats. / Torres, Vicente; Sweeney, William E.; Wang, Xiaofang; Qian, Qi; Harris, Peter C; Frost, Philip; Avner, Ellis D.

In: Kidney International, Vol. 64, No. 5, 11.2003, p. 1573-1579.

Research output: Contribution to journalArticle

Torres, Vicente ; Sweeney, William E. ; Wang, Xiaofang ; Qian, Qi ; Harris, Peter C ; Frost, Philip ; Avner, Ellis D. / EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han : SPRD rats. In: Kidney International. 2003 ; Vol. 64, No. 5. pp. 1573-1579.
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