Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats.
BACKGROUND
Advances in the understanding of cystogenesis, identification of the PKHD1 gene and availability of a rat model (the PCK rat) caused by a Pkhd1 mutation facilitate testing of therapies for autosomal-recessive polycystic kidney disease (ARPKD). Considerable support exists for the importance of the epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha)/EGF receptor (EGFR) axis and of the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) pathway in the pathogenesis of cyst formation and progressive enlargement.


METHODS
To determine whether EGFR tyrosine kinase inhibition is protective in the PCK rat, male and female animals were treated with EKI-785 or EKB-569 or with vehicle alone between 3 and 10 weeks of age. Biochemical and histomorphometric analysis, immunohistochemistry, immunoblotting, enzyme immunoassay, and quantitative reverse transcription-polymerase chain reaction (RT-PCR) were used to ascertain the effects of treatment.


RESULTS
Contrary to other murine models of ARPKD, overexpression and apical mislocalization of EGFR were not detected in the PCK rats. Consistent with these expression results, EKI-785 or EKB-569 administration had no effect or worsened PKD, and had no effect on the development of fibrocystic liver disease. Increased renal cAMP and vasopressin V2 receptor expression were observed in the EKI-785-treated animals.


CONCLUSIONS
EGFR tyrosine kinase inhibition did not protect PCK rats from the development of PKD. This may be due to effects on collecting duct cAMP that counteract possible beneficial effects on the extracellular-regulated protein kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway, particularly in the absence of EGFR overexpression or mislocalization. The relevance of these observations to the treatment of human cystic kidney diseases deserves further study.
Torres
Vicente E
VE
Mayo Foundation, Rochester, Minnesota, USA. torres.vicente@mayo.edu
Sweeney
William E
WE
Wang
Xiaofang
X
Qian
Qi
Q
Harris
Peter C
PC
Frost
Philip
P
Avner
Ellis D
ED
D000634:Aminoquinolines; D000814:Aniline Compounds; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D007274:Injections, Intraperitoneal; D007441:Intubation, Gastrointestinal; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology*; D017044:Polycystic Kidney, Autosomal Recessive / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D012720:Severity of Illness Index
D000634:Aminoquinolines; D000814:Aniline Compounds; D009930:Organic Chemicals; D011799:Quinazolines; D017483:Receptors, Vasopressin; C118029:CL 387785; D000242:Cyclic AMP; D066246:ErbB Receptors; C413879:EKB 569