Faculty Collaboration Database

Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats. Kidney Int 2004 Nov;66(5):1766-73

Date

10/22/2004

Pubmed ID

15496147

DOI

10.1111/j.1523-1755.2004.00952.x

Scopus ID

2-s2.0-16244414716 (requires institutional sign-in at Scopus site)   67 Citations

Abstract

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.

CONCLUSION: 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.

Author List

Torres VE, Sweeney WE Jr, Wang X, Qian Q, Harris PC, Frost P, Avner ED

Author

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aminoquinolines
Aniline Compounds
Animals
Cyclic AMP
Disease Models, Animal
ErbB Receptors
Female
Injections, Intraperitoneal
Intubation, Gastrointestinal
Kidney
Male
Organic Chemicals
Polycystic Kidney, Autosomal Recessive
Quinazolines
Rats
Rats, Inbred Strains
Rats, Sprague-Dawley
Receptors, Vasopressin
Severity of Illness Index