A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1

P. G. Starremans, Xiaogang Li, P. E. Finnerty, L. Guo, A. Takakura, E. G. Neilson, J. Zhou

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Autosomal dominant polycystic kidney disease, a leading cause of end-stage renal disease in adults, is characterized by progressive focal cyst formation in the kidney. Embryonic lethality of Pkd1-targeted mice limits the use of these mice. Here we developed a floxed allele of Pkd1 exons 2-6. Global deletion mutants developed polyhydramnios, hydrops fetalis, polycystic kidney and pancreatic disease. Somatic Pkd1 inactivation in the kidney was achieved by crossing Pkd1flox mice with transgenic mice expressing Cre controlled by a γ-glutamyltranspeptidase promoter. These mutants developed cysts in both proximal and distal nephron segments and survived for about 4 weeks. Somatic loss of heterozygosity was shown in a reporter mouse strain to cause cystogenesis. Some cysts in young mice are positive for multiple tubular markers and a mesenchymal marker, suggesting a delay in tubular epithelial differentiation. A higher cell proliferation rate was observed in distal nephron segments probably accounting for the faster growth rate of distal cysts. Although we observed an overall increase in apoptosis in cystic kidneys, there was no difference between proximal or distal nephron segments. We also found increased cyclic AMP, aquaporin 2 and vasopressin type 2 receptor mRNA levels, and apical membrane translocation of aquaporin 2 in cystic kidneys, all of which may contribute to the differential cyst growth rate observed. The accelerated polycystic kidney phenotype of these mice provides an excellent model for studying molecular pathways of cystogenesis and to test therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)1394-1405
Number of pages12
JournalKidney International
Volume73
Issue number12
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

Fingerprint

Polycystic Kidney Diseases
Cysts
Nephrons
Aquaporin 2
Cystic Kidney Diseases
Polyhydramnios
Hydrops Fetalis
Kidney
Autosomal Dominant Polycystic Kidney
Vasopressin Receptors
Pancreatic Diseases
Molecular Models
Loss of Heterozygosity
Growth
Cyclic AMP
Transgenic Mice
Chronic Kidney Failure
Exons
Alleles
Cell Proliferation

Keywords

  • ADPKD
  • Conditional knockout mouse
  • Cystogenesis
  • Polycystin

ASJC Scopus subject areas

  • Nephrology

Cite this

Starremans, P. G., Li, X., Finnerty, P. E., Guo, L., Takakura, A., Neilson, E. G., & Zhou, J. (2008). A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1. Kidney International, 73(12), 1394-1405. https://doi.org/10.1038/ki.2008.111

A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1. / Starremans, P. G.; Li, Xiaogang; Finnerty, P. E.; Guo, L.; Takakura, A.; Neilson, E. G.; Zhou, J.

In: Kidney International, Vol. 73, No. 12, 01.01.2008, p. 1394-1405.

Research output: Contribution to journalArticle

Starremans, PG, Li, X, Finnerty, PE, Guo, L, Takakura, A, Neilson, EG & Zhou, J 2008, 'A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1', Kidney International, vol. 73, no. 12, pp. 1394-1405. https://doi.org/10.1038/ki.2008.111
Starremans, P. G. ; Li, Xiaogang ; Finnerty, P. E. ; Guo, L. ; Takakura, A. ; Neilson, E. G. ; Zhou, J. / A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1. In: Kidney International. 2008 ; Vol. 73, No. 12. pp. 1394-1405.
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