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This Article Full Text Full Text (PDF) Data Supplements All Versions of this Article: ASN.2006020136v1 17/10/2821    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, L. A. Articles by Ibraghimov-Beskrovnaya, O. Search for Related Content PubMed PubMed Citation Articles by Smith, L. A. Articles by Ibraghimov-Beskrovnaya, O. Related Collections Related Article

Development of Polycystic Kidney Disease in Juvenile Cystic Kidney Mice: Insights into Pathogenesis, Ciliary Abnormalities, and Common Features with Human Disease

Laurie A. Smith^*, Nikolay O. Bukanov^*, Hervé Husson^*, Ryan J. Russo^*, Tiffany C. Barry^*, Ava L. Taylor^*, David R. Beier and Oxana Ibraghimov-Beskrovnaya^*

^* Cell Biology, Genzyme Corporation, Framingham, and Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts

Address correspondence to: Dr. Oxana Ibraghimov-Beskrovnaya, Genzyme Corporation, 5 Mountain Road, Framingham, MA 01701-9322. Phone: 508-270-2134; Fax: 508-620-1203; oxana.beskrovnaya{at}genzyme.com

Received for publication February 10, 2006. Accepted for publication July 18, 2006.

Significant progress in understanding the molecular mechanisms of polycystic kidney disease (PKD) has been made in recent years. Translating this understanding into effective therapeutics will require testing in animal models that closely resemble human PKD by multiple parameters. Similar to autosomal dominant PKD, juvenile cystic kidney (jck) mice develop cysts in multiple nephron segments, including cortical collecting ducts, distal tubules, and loop of Henle. The jck mice display gender dimorphism in kidney disease progression with more aggressive disease in male mice. Gonadectomy experiments show that testosterone aggravates the severity of the disease in jck male mice, while female gonadal hormones have protective effects. EGF receptor is overexpressed and mislocalized in jck cystic epithelia, a hallmark of human disease. Increased cAMP levels in jck kidneys and activation of the B-Raf/extracellular signal–regulated kinase pathway are demonstrated. The effect of jck mutation on the expression of Nek8, a NIMA-related (never in mitosis A) kinase, and polycystins in jck cilia is shown for the first time. Nek8 overexpression and loss of ciliary localization in jck epithelia are accompanied by enhanced expression of polycystins along the cilia. The primary cilia in jck kidneys are significantly more lengthened than the cilia in wild-type mice, suggesting a role for Nek8 in controlling ciliary length. Collectively, these data demonstrate that the jck mice should be useful for testing potential therapies and for studying the molecular mechanisms that link ciliary structure/function and cystogenesis.

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