title: Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1.
abstract: Mouse models for autosomal-dominant polycystic kidney disease (ADPKD), derived from homozygous targeted disruption of Pkd1 gene, generally die in utero or perinatally because of systemic defects. We introduced a loxP site and a loxP-flanked mc1-neo cassette into introns 30 and 34, respectively, of the Pkd1 locus to generate a conditional, targeted mutation. Significantly, before excision of the floxed exons and mc1-neo from the targeted locus by Cre recombinase, mice homozygous for the targeted allele appeared normal at birth but developed polycystic kidney disease with a slower progression than that of Pkd-null mice. Further, the homozygotes continued to produce low levels of full-length Pkd1-encoded protein, suggesting that slight Pkd1 expression is sufficient for renal cyst formation in ADPKD. In this viable model, up-regulation of heparin-binding epidermal growth factor-like growth factor accompanied increased epidermal growth factor receptor signaling, which may be involved in abnormal proliferation of the cyst-lining epithelia. Increased apoptosis in cyst epithelia was only observed in the later period that correlated with the cyst regression. Abnormalities in Na(+)/K(+)-ATPase, aquaporin-2, and vasopressin V2 receptor expression were also identified. This mouse model may be suitable for further studies of progression and therapeutic interventions of ADPKD.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Si-Tse
authors.initials: ST
authors.lastname: Jiang
authors.forename: Yuan-Yow
authors.initials: YY
authors.lastname: Chiou
authors.forename: Ellian
authors.initials: E
authors.lastname: Wang
authors.forename: Hsiu-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Yuan-Ta
authors.initials: YT
authors.lastname: Lin
authors.forename: Ying-Chih
authors.initials: YC
authors.lastname: Chi
authors.forename: Chi-Kuang Leo
authors.initials: CK
authors.lastname: Wang
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.forename: Hung
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051399:Aquaporin 2 / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D050396:TRPP Cation Channels
chemical_list: D051399:Aquaporin 2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D017483:Receptors, Vasopressin; D000254:Sodium-Potassium-Exchanging ATPase; D050396:TRPP Cation Channels; C587884:Hbegf protein, mouse