c-Met and NF-κB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease.
The mechanisms of cystogenesis in autosomal dominant polycystic kidney disease (ADPKD) are not fully understood. Hyperactivation of the tyrosine kinase c-Met contributes to cyst formation, but we do not know the downstream mediators. Here, we found that hyperactivated c-Met led to increased NF-κB signaling, which in turn, drove de novo expression of Wnt7a and overexpression of Wnt7b in Pkd1(-/-) mouse kidneys. Hyperactivated Wnt signaling increased expression of the transcription factor Pax2 in the cells lining cysts. Furthermore, blocking Wnt signaling with DKK1 decreased cyst formation in an organ culture model of ADPKD. In summary, these results suggest that the c-Met/NF-κB/Wnt/Pax2 signaling transduction axis may provide pharmacological targets for the treatment of ADPKD.
Department of Medicine, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. email@example.com
SourceJournal of the American Society of Nephrology : JASN 23:8 2012 Aug pg 1309-18
MeSH8-Bromo Cyclic Adenosine Monophosphate
Organ Culture Techniques
PAX2 Transcription Factor
Polycystic Kidney Diseases
Proto-Oncogene Proteins c-met
TOR Serine-Threonine Kinases
Pub Type(s)Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't