title: Differences in the timing and magnitude of Pkd1 gene deletion determine the severity of polycystic kidney disease in an orthologous mouse model of ADPKD.
abstract: Development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (ADPKD) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes associated with the disease. Using a Pkd1 conditional knockout mouse, we demonstrate that subtly altering the timing and extent of Pkd1 deletion can have a significant impact on the origin and severity of kidney cyst formation. Pkd1 deletion on postnatal day 1 or 2 results in cysts arising from both the cortical and medullary regions, whereas deletion on postnatal days 3-8 results in primarily medullary cyst formation. Altering the extent of Pkd1 deletion by modulating the tamoxifen dose produces dose-dependent changes in the severity, but not origin, of cystogenesis. Limited Pkd1 deletion produces progressive kidney cystogenesis, accompanied by interstitial fibrosis and loss of kidney function. Cyst growth occurs in two phases: an early, rapid growth phase, followed by a later, slow growth period. Analysis of biochemical pathway changes in cystic kidneys reveals dysregulation of the cell cycle, increased proliferation and apoptosis, activation of Mek-Erk, Akt-mTOR, and Wnt-β-catenin signaling pathways, and altered glycosphingolipid metabolism that resemble the biochemical changes occurring in human ADPKD kidneys. These pathways are normally active in neonatal mouse kidneys until repressed around 3 weeks of age; however, they remain active following Pkd1 deletion. Together, this work describes the key parameters to accurately model the pathological and biochemical changes associated with ADPKD in a conditional mouse model.
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rogers
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Moreno
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Smith
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.affiliation: Department of Analytical Research and Development, Sanofi Corporation, Waltham, Massachusetts.
authors.forename: Yeva
authors.initials: Y
authors.lastname: Budman
authors.affiliation: Department of Biostatistics and Programming, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Analytical Research and Development, Sanofi Corporation, Waltham, Massachusetts.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
authors.affiliation: Department of Rare Renal Disease Research, Sanofi-Genzyme R&D Center, Framingham, Massachusetts thomas.natoli@genzyme.com.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Natoli
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D017353:Gene Deletion; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D050396:TRPP Cation Channels
keywords: Cell cycle progression; cyst growth; glycosphingolipid; mouse model; polycystic kidney disease