title: Reactive oxygen species in the presence of high glucose alter ureteric bud morphogenesis.
abstract: Renal malformations are a major cause of childhood renal failure. During the development of the kidney, ureteric bud (UB) branching morphogenesis is critical for normal nephrogenesis. These studies investigated whether renal UB branching morphogenesis is altered by a high ambient glucose environment and studied underlying mechanism(s). Kidney explants that were isolated from different periods of gestation (embryonic days 12 to 18) from Hoxb7-green fluorescence protein mice were cultured for 24 h in either normal d-glucose (5 mM) or high d-glucose (25 mM) medium with or without various inhibitors. Alterations in renal morphogenesis were assessed by fluorescence microscopy. Paired-homeobox 2 (Pax-2) gene expression was determined by real-time quantitative PCR, Western blotting, and immunohistology. The results revealed that high d-glucose (25 mM) specifically stimulates UB branching morphogenesis via Pax-2 gene expression, whereas other glucose analogs, such as d-mannitol, l-glucose, and 2-deoxy-d-glucose, had no effect. The stimulatory effect of high glucose on UB branching was blocked in the presence of catalase and inhibitors of NADPH oxidase, mitochondrial electron transport chain complex I, and Akt signaling. Moreover, in in vivo studies, it seems that high glucose induces, via Pax-2 (mainly localized in UB), acceleration of UB branching but not nephron formation. Taken together, these data demonstrate that high glucose alters UB branching morphogenesis. This occurs, at least in part, via reactive oxygen species generation, activation of Akt signaling, and upregulation of Pax-2 gene expression.
authors.affiliation: University of Montreal, Centre hospitalier de l'Université de Montréal-Hôtel-Dieu, Pavillon Masson, Montreal, Quebec, Canada. shao.ling.zhang@umontreal.ca
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Stella
authors.initials: S
authors.lastname: Tran
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chenier
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hébert
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
mesh_terms: D000818:Animals; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology*; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D051762:PAX2 Transcription Factor / Q000235:genetics; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D014513:Ureter / Q000187:drug effects* / Q000196:embryology*
chemical_list: D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D017382:Reactive Oxygen Species; D005947:Glucose