Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1

Si Tse Jiang, Yuan Yow Chiou, Ellian Wang, Hsiu Kuan Lin, Yuan Ta Lin, Ying Chih Chi, Chi Kuang Leo Wang, Ming Jer Tang, Hung Li

Research output: Contribution to journalArticlepeer-review

81 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)205-220
Number of pages16
JournalAmerican Journal of Pathology
Volume168
Issue number1
DOIs
Publication statusPublished - 2006 Jan

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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