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.
Sweeney
W E
WE
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio 44106-6003, USA.
Futey
L
L
Frost
P
P
Avner
E D
ED
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D009399:Nephrons / Q000166:cytology / Q000187:drug effects; D009924:Organ Culture Techniques / Q000379:methods*; D010766:Phosphorylation; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011799:Quinazolines; D004815:Epidermal Growth Factor; C118029:CL 387785; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases