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-kB signaling, which in turn, drove de novo expression of Wnt7a and overexpression of Wnt7b in Pkd1 2/2 mouse kidneys. Hyperactivated Wnt signaling increased expression of the transcription factor Pax2 in thecellsliningcysts.Furthermore,blockingWntsignalingwithDKK1decreasedcystformationinanorgan culture model of ADPKD. In summary, these results suggest that the c-Met/NF-kB/Wnt/Pax2 signaling transduction axis may provide pharmacological targets for the treatment of ADPKD.