c-Met and NF-κB―Dependent Overexpression of Wnt7a and -7b and Pax2 Promotes Cystogenesis in Polycystic Kidney Disease

• Published in: Journal of the American Society of Nephrology 2012-08, Vol.23 (8), p.1309-1318
• Main Authors: SHAN QIN, TAGLIENTI, Mary, LEI CAI, JING ZHOU, KREIDBERG, Jordan A
• Format: Article
• Language: English
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Basic Research; Biological and medical sciences; Female; Kidneys; Male; Malformations of the urinary system; Medical sciences; Mice; Mice, Knockout; Nephrology. Urinary tract diseases; NF-kappa B - metabolism; Organ Culture Techniques; PAX2 Transcription Factor - metabolism; Polycystic Kidney Diseases - etiology; Polycystic Kidney Diseases - metabolism; Pregnancy; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-met - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Up-Regulation; Wnt Proteins - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2011030277

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.