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Pkd1-targeted mutation reveals a role for the Wolffian duct in autosomal dominant polycystic kidney disease

Published online by Cambridge University Press:  15 August 2019

J. B. Tee ,
A. V. Dnyanmote ,
M. K. Lorenzo ,
O. R. Lee ,
S. Grisaru ,
M. Suk  and
P. D. Acott
J. B. Tee*
Affiliation:
Department of Pediatrics, IWK Health Centre – Dalhousie University, 5850 University Ave, Halifax, NS, B3K 6R8, Canada
A. V. Dnyanmote
Affiliation:
Department of Pediatrics, IWK Health Centre – Dalhousie University, 5850 University Ave, Halifax, NS, B3K 6R8, Canada
M. K. Lorenzo
Affiliation:
Department of Pediatrics, Hospital for Sick Children – University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8Canada
O. R. Lee
Affiliation:
Department of Family Medicine, University of Alberta, 8215 - 112 St., Edmonton, AB, T6G 2R3Canada
S. Grisaru
Affiliation:
Department of Pediatrics, Alberta Children’s Hospital – University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB, T3B 6A9Canada
M. Suk
Affiliation:
Department of Family Medicine, University of Alberta, 8215 - 112 St., Edmonton, AB, T6G 2R3Canada
P. D. Acott
Affiliation:
Department of Pediatrics, IWK Health Centre – Dalhousie University, 5850 University Ave, Halifax, NS, B3K 6R8, Canada
*
Address for correspondence: J. B. Tee, Department of Pediatrics, IWK Health Centre – Dalhousie University, 5850 University Ave, Halifax, NS, Canada. Email: james.tee@iwk.nshealth.ca
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Abstract

Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

Keywords

Polycystic kidneyWolffian ductkidney developmentPkd1microRNAs
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 11 , Issue 1 , February 2020 , pp. 78 - 85
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2019 

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