TY - JOUR
T1 - Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1
AU - Jiang, Si Tse
AU - Chiou, Yuan Yow
AU - Wang, Ellian
AU - Lin, Hsiu Kuan
AU - Lin, Yuan Ta
AU - Chi, Ying Chih
AU - Wang, Chi Kuang Leo
AU - Tang, Ming Jer
AU - Li, Hung
N1 - Funding Information:
Supported by The National Research Program for Genomic Medicine (grant AS92IMB3 ) and the National Health Research Institute (postdoctoral fellowship award RE91N004 to S.-T.J. ).
PY - 2006/1
Y1 - 2006/1
N2 - 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.
AB - 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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U2 - 10.2353/ajpath.2006.050342
DO - 10.2353/ajpath.2006.050342
M3 - Article
C2 - 16400024
AN - SCOPUS:30344471203
SN - 0002-9440
VL - 168
SP - 205
EP - 220
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -