Original Article
Kidney International (1999) 56, 406–413; doi:10.1046/j.1523-1755.1999.00577.x
In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor
William E Sweeney, Lidia Futey, Phillip Frost and Ellis D Avner
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, and Wyeth-Ayerst Research, Pearl River, New York, USA
Correspondence: Ellis D Avner, M.D., Department of Pediatrics, Rainbow Babies and Children's Hospital, 11100 Euclid Avenues LC 6003, Cleveland, Ohio 44106-6003, USA. E-mail: eda@po.cwru.edu
Received 8 December 1998; Revised 25 February 1999; Accepted 5 March 1999.
Abstract
In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor.
Background
Recessively transmitted polycystic kidney disease (PKD) in many murine models is characterized by the initial formation of proximal tubular cysts (stage 1), followed by growth and enlargement of renal collecting tubule (CT) cysts (stage 2). Previous studies have reported that stage 1 cyst formation and growth could be manipulated in vitro by using embryonic kidney explants and newborn explant microslices in organ culture.
Methods
Microslices of postnatal kidneys cultured on Transwell tissue culture inserts allow experimental manipulation of stage 2 CT cyst development and growth. This system was used to test a potential therapeutic compound for treatment of PKD. This compound, EKI-785, modulates altered epidermal growth factor receptor (EGFR) expression in CT cysts by inhibition of EGFR autophosphorylation.
Results
These studies demonstrate that: (a) minor modifications of the previously described organ culture system permit successful culture of more mature renal tissue, and (b) cystic explants treated with EGF and EKI-785 demonstrated a marked reduction in CT cystic lesions compared with cystic explants treated with EGF alone.
Conclusions
This study suggests that pharmacological strategies can be used to decrease EGFR tyrosine kinase activity and CT cyst formation and enlargement in murine PKD.
Keywords:
autosomal recessive polycystic kidney disease, PKD, epidermal growth factor, tyrosine kinase inhibitor, collecting tubule cysts, organ culture
