Unbound MEDLINE

c-Met and NF-κB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease.

Abstract

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.

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  • Publisher Full Text

    • Authors

    Qin S, Taglienti M, Cai L, Zhou J, Kreidberg JA

    Institution

    Department of Medicine, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. shan.qin@childrens.harvard.edu

    Source

    Journal of the American Society of Nephrology : JASN 23:8 2012 Aug pg 1309-18

    MeSH

    8-Bromo Cyclic Adenosine Monophosphate
    Animals
    Female
    Male
    Mice
    Mice, Knockout
    NF-kappa B
    Organ Culture Techniques
    PAX2 Transcription Factor
    Polycystic Kidney Diseases
    Pregnancy
    Proto-Oncogene Proteins
    Proto-Oncogene Proteins c-met
    Signal Transduction
    TOR Serine-Threonine Kinases
    Up-Regulation
    Wnt Proteins

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22677559