Hostname: page-component-78c5997874-ndw9j Total loading time: 0 Render date: 2024-11-19T05:52:55.173Z Has data issue: false hasContentIssue false
  • English
  • Français

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: [email protected]
Get access Rights & Permissions [Opens in a new window]

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 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

NIH Publication No. 10–3895 2010; Available from: http://kidney.niddk.nih.gov/.Google Scholar
Davies, F, Coles, GA, Harper, PS, Williams, AJ, Evans, C, Cochlin, D. Polycystic kidney disease re-evaluated: a population-based study. Q J Med. 1991; 79, 477–485.Google ScholarPubMed
Tee, JB, Acott, PD, McLellan, DH, Crocker, JF. Phenotypic heterogeneity in pediatric autosomal dominant polycystic kidney disease at first presentation: a single-center, 20-year review. Am J Kidney Dis. 2004; 43, 296–303.CrossRefGoogle ScholarPubMed
Rossetti, S, Consugar, MB, Chapman, AB, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007; 18, 2143–2160.CrossRefGoogle ScholarPubMed
Al-Bhalal, L, Akhtar, M. Molecular basis of autosomal dominant polycystic kidney disease. Adv Anat Pathol. 2005; 12, 126–133.CrossRefGoogle ScholarPubMed
Boletta, A, Qian, F, Onuchic, LF, et al. Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells. Mol Cell. 2000; 6, 1267–1273.CrossRefGoogle ScholarPubMed
Praetorius, HA, Frokiaer, J, Nielsen, S, Spring, KR. Bending the primary cilium opens Ca2+sensitive intermediate-conductance K+ channels in MDCK cells. J Membr Biol. 2003; 191, 193–200.CrossRefGoogle ScholarPubMed
Praetorius, HA, Spring, KR. Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol. 2003; 191, 69–76.CrossRefGoogle ScholarPubMed
Praetorius, HA, Spring, KR. Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol. 2001; 184, 71–79.CrossRefGoogle ScholarPubMed
Lin, F, Hiesberger, T, Cordes, K, et al. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U S A. 2003; 100, 5286–5291.CrossRefGoogle ScholarPubMed
Yoder, BK, Hou, X, Guay-Woodford, LM. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol. 2002; 13, 2508–2516.CrossRefGoogle ScholarPubMed
Pei, Y. A “two-hit” model of cystogenesis in autosomal dominant polycystic kidney disease? Trends Mol Med. 2001; 7, 151–156.CrossRefGoogle ScholarPubMed
Qian, F, Watnick, TJ, Onuchic, LF, Germino, GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996; 87, 979–987.CrossRefGoogle ScholarPubMed
Koptides, M, Constantinides, R, Kyriakides, G, et al. Loss of heterozygosity in polycystic kidney disease with a missense mutation in the repeated region of PKD1. Hum Genet. 1998; 103, 709–717.CrossRefGoogle ScholarPubMed
Badenas, C, Torra, R, Perez-Oller, L, et al. Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients. Eur J Hum Genet. 2000; 8, 487–492.CrossRefGoogle ScholarPubMed
Ong, AC, Harris, PC, Davies, DR, et al. Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue. Kidney Int. 1999; 56, 1324–1333.CrossRefGoogle ScholarPubMed
Lanoix, J, D’Agati, V, Szabolcs, M, Trudel, M. Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). Oncogene. 1996; 13, 1153–1160.Google Scholar
Cuellar, TL, McManus, MT. MicroRNAs and endocrine biology. J Endocrinol. 2005; 187, 327–332.CrossRefGoogle ScholarPubMed
Sun, W, Julie Li, YS, Huang, HD, Shyy, JY, Chien, S. microRNA: a master regulator of cellular processes for bioengineering systems. Annu Rev Biomed Eng. 2010; 12, 1–27.CrossRefGoogle ScholarPubMed
Janga, SC, Vallabhaneni, S. MicroRNAs as post-transcriptional machines and their interplay with cellular networks. Adv Exp Med Biol. 2011; 722, 59–74.CrossRefGoogle ScholarPubMed
Lewis, BP, Burge, CB, Bartel, DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120, 15–20.CrossRefGoogle ScholarPubMed
Pandey, P, Qin, S, Ho, J, Zhou, J, Kreidberg, JA. Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease. BMC Syst Biol. 2011; 5, 56.CrossRefGoogle ScholarPubMed
Nagalakshmi, VK, Ren, Q, Pugh, MM, Valerius, MT, McMahon, AP, Yu, J. Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. Kidney Int. 2011; 79, 317–330.CrossRefGoogle ScholarPubMed
Pastorelli, LM, Wells, S, Fray, M, et al. Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract. Mamm Genome. 2009; 20, 140–151.CrossRefGoogle ScholarPubMed
Wang, E, Hsieh-Li, HM, Chiou, YY, et al. Progressive renal distortion by multiple cysts in transgenic mice expressing artificial microRNAs against Pkd1. J Pathol. 2010; 222, 238–248 doi: 10.1002/path.2765.CrossRefGoogle ScholarPubMed
Lu, W, Peissel, B, Babakhanlou, H, et al. Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation. Nat Genet. 1997; 17, 179–181.CrossRefGoogle ScholarPubMed
Arnaout, MA. The vasculopathy of autosomal dominant polycystic kidney disease: insights from animal models. Kidney Int. 2000; 58, 2599–2610.CrossRefGoogle ScholarPubMed
Kim, K, Drummond, I, Ibraghimov-Beskrovnaya, O, Klinger, K, Arnaout, MA. Polycystin 1 is required for the structural integrity of blood vessels. Proc Natl Acad Sci U S A. 2000; 97, 1731–1736.CrossRefGoogle ScholarPubMed
Boulter, C, Mulroy, S, Webb, S, Fleming, S, Brindle, K, Sandford, R. Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc Natl Acad Sci U S A. 2001; 98, 12174–12179.CrossRefGoogle ScholarPubMed
Piontek, KB, Huso, DL, Grinberg, A, et al. A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J Am Soc Nephrol. 2004; 15, 3035–3043.CrossRefGoogle ScholarPubMed
Shah, MM, Tee, JB, Meyer, T, et al. The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects. Am J Physiol Renal Physiol. 2009; 297, F1330–F1341.CrossRefGoogle ScholarPubMed
Palsson, R, Sharma, CP, Kim, K, McLaughlin, M, Brown, D, Arnaout, MA. Characterization and cell distribution of polycystin, the product of autosomal dominant polycystic kidney disease gene 1. Mol Med. 1996; 2, 702–711.CrossRefGoogle ScholarPubMed
Laboratories, J. Mouse strain B6.129S4-Pkd1tm2Ggg/J. 2015; Available from: http://jaxmice.jax.org/strain/010671.html.Google Scholar
Carroll, TJ, Park, JS, Hayashi, S, Majumdar, A, McMahon, AP. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell. 2005; 9, 283–292.CrossRefGoogle Scholar
Kress, C, Vogels, R, De Graaff, W, et al. Hox-2.3 upstream sequences mediate lacZ expression in intermediate mesoderm derivatives of transgenic mice. Development. 1990; 109, 775–786.Google ScholarPubMed
Han, Y, Chen, J, Zhao, X, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing. PLoS One. 2011; 6, e18286.CrossRefGoogle ScholarPubMed
Meyer, SU, Pfaffl, MW, Ulbrich, SE. Normalization strategies for microRNA profiling experiments: a 'normal’ way to a hidden layer of complexity? Biotechnol lett. 2010; 32, 1777–1788.
Mortazavi, A, Williams, BA, McCue, K, Schaeffer, L, Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008; 5, 621–628.CrossRefGoogle ScholarPubMed
Fabregat, A, Jupe, S, Matthews, L, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2018; 46, D649–D655.CrossRefGoogle ScholarPubMed
Fan, Y, Siklenka, K, Arora, SK, Ribeiro, P, Kimmins, S, Xia, J. miRNet – dissecting miRNA-target interactions and functional associations through network-based visual analysis. Nucleic Acids Res. 2016;44, W135–W141.CrossRefGoogle ScholarPubMed
Garcia-Gonzalez, MA, Outeda, P, Zhou, Q, et al. Pkd1 and Pkd2 are required for normal placental development. PLoS One. 2010; 5, e12821.CrossRefGoogle ScholarPubMed
Lu, W, Shen, X, Pavlova, A, et al. Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum Mol Genet. 2001; 10, 2385–2396.CrossRefGoogle ScholarPubMed
Wang, Y, Chen, L, Chen, B, et al. Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network. Cell Death Dis. 2013; 4, e765.CrossRefGoogle ScholarPubMed
Cui, T, Zhang, L, Huang, Y, et al. MNDR v2.0: an updated resource of ncRNA-disease associations in mammals. Nucleic Acids Res. 2018; 46, D371–D374.Google ScholarPubMed
Gabow, PA. Autosomal dominant polycystic kidney disease. N Engl J Med. 1993; 329, 332–342.CrossRefGoogle ScholarPubMed
Reed, BY, McFann, K, Bekheirnia, MR, et al. Variation in age at ESRD in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2008; 51, 173–183.CrossRefGoogle ScholarPubMed
Shamshirsaz, AA, Reza Bekheirnia, M, Kamgar, M, et al. Autosomal-dominant polycystic kidney disease in infancy and childhood: progression and outcome. Kidney Int. 2005; 68, 2218–2224.CrossRefGoogle ScholarPubMed
Grantham, JJ, Cook, LT, Wetzel, LH, Cadnapaphornchai, MA, Bae, KT. Evidence of extraordinary growth in the progressive enlargement of renal cysts. Clin J Am Soc Nephrol. 2010; 5, 889–896.CrossRefGoogle ScholarPubMed
Igarashi, P, Somlo, S. Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2002; 13, 2384–2398.CrossRefGoogle ScholarPubMed
Torres, VE, Harris, PC, Pirson, Y. Autosomal dominant polycystic kidney disease. Lancet. 2007; 369, 1287–1301.CrossRefGoogle ScholarPubMed
Zhou, J. Polycystins and primary cilia: primers for cell cycle progression. Annu Rev Physiol. 2009; 71, 83–113.CrossRefGoogle ScholarPubMed
Piontek, K, Menezes, LF, Garcia-Gonzalez, MA, Huso, DL, Germino, GG. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med. 2007; 13, 1490–1495.CrossRefGoogle ScholarPubMed