title: Hyperglycemia in the absence of cilia accelerates cystogenesis and induces renal damage.
abstract: In polycystic kidney disease (PKD), the rate of cyst formation and disease progression is highly variable. The lack of predictability in disease progression may be due to additional environmental factors or pathophysiological processes called "third hits." Diabetes is a growing epidemic, and recent studies suggest that PKD patients may be at an increased risk for this disease. We sought to determine if hyperglycemia enhances the initiation and rate of cystogenesis. Tamoxifen was administered to adult Ift88 conditional floxed allele mice to induce cilia loss in the presence of Cre. Subsequent administration of streptozotocin resulted in equivalent hyperglycemia in cilia(+) and cilia(-) mice. Hyperglycemia with loss of cilia increased the rate of cyst formation and cell proliferation. Structural and functional alterations in the kidney, including focal glomerular foot process effacement, interstitial inflammation, formation of primitive renal tubules, polyuria, and increased proteinuria, were also observed in hyperglycemic cilia(-) mice. Gene array analysis indicated enhanced Wnt and epithelial-to-mesenchymal transition signaling in the kidney of hyperglycemic cilia(-) mice. These data show that hyperglycemia, in the absence of cilia, results in renal structural and functional damage and accelerates cystogenesis, suggesting that diabetes is a risk factor in the progression of PKD.
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; sask@med.umich.edu.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Sas
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Fitzgibbon
authors.affiliation: Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Catalin F
authors.initials: CF
authors.lastname: Baicu
authors.affiliation: Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina; Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina; Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Steele
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: May
authors.initials: M
authors.lastname: Amria
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Saigusa
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Jason
authors.initials: J
authors.lastname: Funk
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Bunni
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Siroky
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
authors.affiliation: Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina; Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006439:Hemodynamics; D006943:Hyperglycemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D018345:Mice, Knockout; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000473:pathology; D011897:Random Allocation; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D051153:Wnt Proteins
keywords: Wnt; diabetes; epithelial-to-mesenchymal transition; polycystic kidney disease; streptozotocin