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Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients.

ABSTRACT: Kidney disease, a common complication of diabetes, associates with poor prognosis. Our previous animal model studies linked aquaporin (AQP)11 to acute kidney injury, hyperglycemia-induced renal impairment, and kidney disease in diabetes. Here, we report the AQP11 rs2276415 variant as a genetic factor placing type 2 diabetic patients at greater risk for the development of kidney disease. We performed two independent retrospective case-control studies in 1,075 diabetic and 1,619 nondiabetic individuals who were identified in the Synthetic Derivative Database with DNA samples in the BioVU DNA repository at Vanderbilt University (Nashville, TN). A ?(2)-test and multivariable logistic regression analysis with adjustments for age, sex, baseline serum creatinine, and underlying comorbid disease covariates showed a significant association between rs2276415 and the prevalence of any event of acute kidney injury and chronic kidney disease (CKD) in diabetic patients but not in patients without diabetes. This result was replicated in the second independent study. Diabetic CKD patients over 55 yrs old with the minor AQP11 allele had a significantly faster progression of estimated glomerular filtration rate decline than patients with the wild-type genotype. Three-dimensional structural analysis suggested a functional impairment of AQP11 with rs2276415, which could place diabetic patients at a higher risk for kidney disease. These studies identified rs2276415 as a candidate genetic factor predisposing patients with type 2 diabetes to CKD.

SUBMITTER: Choma DP

PROVIDER: S-EPMC4773830 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients.

Choma David P DP Vanacore Roberto R Naylor Helen H Zimmerman Ian A IA Pavlichenko Andrei A Pavlichenko Artyom A Foye Liberty L Carbone David P DP Harris Raymond C RC Dikov Mikhail M MM Tchekneva Elena E EE

American journal of physiology. Renal physiology 20151230 5

Kidney disease, a common complication of diabetes, associates with poor prognosis. Our previous animal model studies linked aquaporin (AQP)11 to acute kidney injury, hyperglycemia-induced renal impairment, and kidney disease in diabetes. Here, we report the AQP11 rs2276415 variant as a genetic factor placing type 2 diabetic patients at greater risk for the development of kidney disease. We performed two independent retrospective case-control studies in 1,075 diabetic and 1,619 nondiabetic indivi ...[more]

PMID: 26719361

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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 variant associates with kidney disease in type 2 diabetic patients.

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Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients.

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