title: Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease.
abstract: 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.
authors.affiliation: Genzyme Corporation, 5 Mountain Road, Framingham, MA 01701-9322, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Smith
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Russo
authors.forename: Tiffany C
authors.initials: TC
authors.lastname: Barry
authors.forename: Ava L
authors.initials: AL
authors.lastname: Taylor
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
mesh_terms: D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D002925:Ciliary Motility Disorders / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D052177:Kidney Diseases, Cystic / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000072379:NIMA-Related Kinases; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology* / Q000503:physiopathology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012727:Sex Characteristics; D015398:Signal Transduction; D015996:Survival Rate; D050396:TRPP Cation Channels / Q000378:metabolism
chemical_list: D012739:Gonadal Steroid Hormones; D050396:TRPP Cation Channels; D000242:Cyclic AMP; D011494:Protein Kinases; D000072379:NIMA-Related Kinases; C499219:Nek8 protein, mouse; D017346:Protein Serine-Threonine Kinases