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. shan.qin@childrens.harvard.edu
Shan
S
Qin
Mary
M
Taglienti
Lei
L
Cai
Jing
J
Zhou
Jordan A
JA
Kreidberg
D015124:8-Bromo Cyclic Adenosine Monophosphate; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009924:Organ Culture Techniques; D051762:PAX2 Transcription Factor / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000209:etiology / Q000378:metabolism*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*
D016328:NF-kappa B; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; C095937:Wnt7b protein, mouse; D015124:8-Bromo Cyclic Adenosine Monophosphate; C546843:mTOR protein, mouse; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases