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- Title
Heterozygous Pkd1 mutation induces abnormal EGFR signaling.
- Authors
Amsler, Kurt; Hyink, Deborah; Wilson, Patricia D.
- Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) in humans, caused by heterozygous mutation of the PKD1 or PKD2 genes, leads to progressive renal cyst expansion and renal failure. ADPKD renal tissue exhibits abnormal activation of signaling proteins including ERK ½ and JNK ½. Homozygous Pkd1 mutant mouse embryos die at gestational day E14-E16. The embryos uniformly exhibit severe edema and hemorrhage but variability in macroscopic cyst formation. Heterozygous Pkd1 mutant mice are viable but macroscopic cysts are occasionally observed in older mice, greater than 9 months. Cyst expansion in heterozygous Pkd1 mutant mice is slowed by inhibition of erbB2 receptor tyrosine kinase activity. Renal tubules from heterozygous Pkd1 mutant mice exhibit increased phosphorylation of the Epidermal Growth Factor Receptor (EGFR) and increased activation of ERK ½ and JNK ½. Primary renal cell populations restrict paracellular solute movement. Populations from heterozygous Pkd1 mutant mice exhibit enhanced EGF-dependent activation of ERK ½. These results indicate that heterozygous Pkd1 mutation in renal epithelial cells induces EGFR hyperactivation and enhanced EGF-dependent signaling.
- Subjects
GENETIC mutation; EPIDERMAL growth factor; POLYCYSTIC kidney disease; PHOSPHORYLATION; EPITHELIAL cells; LABORATORY mice
- Publication
FASEB Journal, 2007, Vol 21, Issue 5, pA504
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.5.a504-d