Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1.
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.
Pubmed ID: 16400024 RIS Download
Animals | Apoptosis | Aquaporin 2 | Blotting, Western | Disease Models, Animal | Epidermal Growth Factor | Heparin-binding EGF-like Growth Factor | Immunohistochemistry | In Situ Nick-End Labeling | Intercellular Signaling Peptides and Proteins | Mice | Mice, Knockout | Mutation | Polycystic Kidney Diseases | Proteins | Receptor, Epidermal Growth Factor | Receptors, Vasopressin | Reverse Transcriptase Polymerase Chain Reaction | Sodium-Potassium-Exchanging ATPase | TRPP Cation Channels