title: Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by large fluid-filled cysts and progressive deterioration of renal function necessitating renal replacement therapy. Previously, we generated a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model and showed that inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Therefore, we hypothesized that injury-induced tubular epithelial cell proliferation may accelerate cyst formation in the kidneys of adult Pkd1-deletion mice. Mice were treated with the nephrotoxicant 1,2-dichlorovinyl-cysteine (DCVC) after Pkd1-gene inactivation, which indeed accelerated cyst formation significantly. After the increased proliferation during tissue regeneration, proliferation decreased to basal levels in Pkd1-deletion mice just as in DCVC-treated controls. However, in severe cystic kidneys, 10-14 weeks after injury, proliferation increased again. This biphasic response suggests that unrestricted cell proliferation after injury is not the underlying mechanism for cyst formation. Aberrant planar cell polarity (PCP) signaling and increased canonical Wnt signaling are suggested to be involved in cyst formation. Indeed, we show here that in Pkd1 conditional deletion mice expression of the PCP component Four-jointed (Fjx1) is decreased while its expression is required during tissue regeneration. In addition, we show that altered centrosome position and the activation of canonical Wnt signaling are early effects of Pkd1-gene disruption. This suggests that additional stimuli or events are required to trigger the process of cyst formation. We propose that during tissue repair, the integrity of the newly formed Pkd1-deficient cells is modified rendering them susceptible to subsequent cyst formation.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Hester
authors.initials: H
authors.lastname: Happé
authors.forename: Wouter N
authors.initials: WN
authors.lastname: Leonhard
authors.forename: Annemieke
authors.initials: A
authors.lastname: van der Wal
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.forename: Irma S
authors.initials: IS
authors.lastname: Lantinga-van Leeuwen
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007684:Kidney Tubules / Q000166:cytology* / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D050396:TRPP Cation Channels; D051153:Wnt Proteins; C119155:Fjx1 protein, mouse