Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 23, Issue 8, Pages 1309-1318Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2011030277
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Funding
- American Heart Association [09SDG2170031]
- National Kidney Foundation serving New England
- Polycystic Kidney Disease Foundation [180F08b]
- National Institutes of Health [P50DK074030, DK51050, DK074030, DK40703, DK50118-01]
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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-kappa B 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-kappa B/Wnt/Pax2 signaling transduction axis may provide pharmacological targets for the treatment of ADPKD.
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