Differences in cell proliferation in the cpk and Pkd1 mouse models of polycystic kidney disease

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Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common potentially fatal single gene disorders, resulting from mutations in either the Pkd1 or Pkd2 gene. Renal pathologies found in ADPKD include cysts resulting from increased fluid secretion, cell proliferation, and apoptosis, with an altered differentiation of the epithelial cells lining the cysts. In humans, ADPKD is thought to result from an inherited mutation in the PKD1 gene, followed by a somatic “second hit” mutation in the normal allele. The mechanism of this second hit is not understood. We analyzed the genomic sequence of human PKD1 and found extensive tandem repeats of guanine capable of supporting guanine quadruplex (G4) structures. G4 DNA is four‐stranded, and it is known to functionally contribute to recombination and mutagenesis. By comparison, mice do not carry extensive G4 repeats in the Pkd1 gene, thus targeted deletion of both Pkd1 alleles are required to generate cysts. However, homozygous Pkd1 null mice are embryonically lethal. Therefore, we have generated mice carrying a kidney specific deletion of the Pkd1 gene, called Pkd1CD. These mice develop rapid cystic disease and die by 14 days of age. Another commonly studied mouse model of PKD is a mutation in the cystin gene (cpk mice), which is a mouse model of ARPKD. These mice have a complete loss of the cystin gene, however, they survive until about three weeks of age. To begin to determine the differences in disease progression between the Pkd1CD mice and the cpk mice, we evaluated cell proliferation in these two models of PKD. While kidneys isolated from Pkd1CD mice showed high levels of cell proliferation in the cyst lining cells, similarly cystic kidneys from cpk mice showed very little cell proliferation in the cyst lining cells. Moreover, we observed differences between PCNA and Ki67 labeling as markers for cell proliferation in both mouse models. Because these mouse models differ significantly from human ADPKD, future studies will include replacing portions of the mouse PKD1 gene with the human PKD1 gene that includes the G4 repeats.Support or Funding InformationNIH DK100972This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.