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(American Journal of Pathology. 2006;168:205-220.)
© 2006 American Society for Investigative Pathology

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 and Hung Li^*

From the Institute of Molecular Biology,^* Academia Sinica, Taipei; the Department of Pediatrics, Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan; the Department of Physiology, National Cheng Kung University Medical College, Tainan; and the Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan

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.

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