title: Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress.
abstract: Aquaporin 11 (AQP11) is a newly described member of the protein family of transport channels. AQP11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse AQP11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of AQP11 oligomeric structure. AQP11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11 mutant mice developed PT-specific mitochondrial injury. Glucose increased AQP11 protein expression in wild-type kidney and upregulation of AQP11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total AQP11 levels in heterozygotes were higher than in wild-type mice but were not further increased in response to glucose. In Aqp11 insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11 mutation carriers. Phenotypically normal mice heterozygous for the Aqp11 mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that were prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for AQP11 to prevent glucose-induced oxidative stress in proximal tubules.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Atochina-Vasserman
authors.forename: Asel
authors.initials: A
authors.lastname: Biktasova
authors.forename: Elena
authors.initials: E
authors.lastname: Abramova
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.forename: Saki
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sonoda
authors.forename: Liberty
authors.initials: L
authors.lastname: Foye
authors.forename: Christo
authors.initials: C
authors.lastname: Venkov
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ryzhov
authors.forename: Sergey
authors.initials: S
authors.lastname: Novitskiy
authors.forename: Natalia
authors.initials: N
authors.lastname: Shlonimskaya
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikeda
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.forename: Elena E
authors.initials: EE
authors.lastname: Tchekneva
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C503878:Aqp11 protein, mouse; D020346:Aquaporins; D017382:Reactive Oxygen Species
keywords: acute kidney injury; protein oligomerization; proximal tubules