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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.

SUBMITTER: Atochina-Vasserman EN

PROVIDER: S-EPMC3651623 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress.

Atochina-Vasserman Elena N EN Biktasova Asel A Abramova Elena E Cheng Dong-Sheng DS Polosukhin Vasiliy V VV Tanjore Harikrishna H Takahashi Saki S Sonoda Hiroko H Foye Liberty L Venkov Christo C Ryzhov Sergey V SV Novitskiy Sergey S Shlonimskaya Natalia N Ikeda Masahiro M Blackwell Timothy S TS Lawson William E WE Gow Andrew J AJ Harris Raymond C RC Dikov Mikhail M MM Tchekneva Elena E EE

American journal of physiology. Renal physiology 20130313 10

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 ...[more]

PMID: 23486012

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Project description:Aquaporin-11 (AQP11), a new member of the aquaporin family, is localized in the endoplasmic reticulum (ER). Aqp11â/â mice neonatally suffer from polycystic kidneys derived from the proximal tubule. Its onset is proceeded by the vacuolization of ER. However, the mechanism for the formation of vacuoles and the development of cysts remain to be clarified. Here, we show that Aqp11â/â mice and polycystic kidney disease animals share a common pathogenic mechanism of cyst formation. Experiment Overall Design: Aqp11+/â mice, originally generated in a 129/SvEvBrd background (4), were back-crossed 10â11 times to a C57/BL6 background. Heterozygous mice were interbred to obtain knockout (Aqp11â/â) and wild-type littermates (Aqp11+/+). The genotypes of offsprings were analyzed by PCR using tail DNA as a template. All animal experiments were approved by the Animal Care Committee of the University of Tokyo. One-week-old mice were sacrificed by cervical dislocation. Kidneys were rapidly excised on ice, washed in ice-cold phosphate-buffered saline, immersed in RNAlater (Ambion) and stored at â20Â°C. Total RNA was isolated using TRIzol Reagent (Invitrogen) and cleaned up using an RNeasy minikit with DNase treatment (Qiagen). The RNA quality and quantity were examined by agarose-gel electrophoresis and a spectrophotometer (GE Healthcare). Five pairs of Aqp11+/â mice were interbred, and we obtained 7 Aqp11+/+ and 9 Aqp11â/â offsprings. Three micrograms of total RNA obtained from each kidney was individually reverse-transcribed, amplified, and labeled using GeneChip One-Cycle Target Labeling and Control Reagent package (Affymetrix) according to the manufacturerâs protocol. Labeled cRNA was hybridized to GeneChip Mouse Genome 430 2.0 Array (Affymetrix) (a total of 16 samples on 16 different arrays). The arrays were washed, stained using Fluidics Station (Affymetrix), and then scanned with the GeneChip Scanner (Affymetrix). Data collection was performed using GeneChip Operating Software (Affymetrix). The quality of collected data was checked by scatter plot analysis.

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Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress.

Publications

Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress.

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