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• W4315702962 abstract "Objective: Recently administration of non-steroidal mineralocorticoid receptor (MR) antagonist with maximal tolerable doses of the renin-angiotensin system inhibitors significantly reduced renal as well as cardiovascular composite outcomes in patients with type 2 diabetes and chronic kidney diseases. However, molecular mechanisms of how MR is activated are not understood. Post-translational modification of O-linked-N-acetylglucosamine (O-GlcNAc) has emerged as an essential glucose-sensing mechanism. The aim of this study was to clarify whether MR is modified by O-GlcNAc and figure out the significance of this modification on MR in the context of diabetes mellitus. Design and method: 1) The MR transcriptional activities were investigated in reporter assays and real time RT-PCR. Levels of expression of MR were examined with western blot analysis. Cells were cultured in 5 mM or 30 mM glucose conditions and additionally treated with PUGNAc, an O-GlcNAcase inhibitor, or 6-diazo-5-oxonorleucine (DON), a glucosamine-fructose-6-phosphate amidotransferase inhibitor. 2) O-GlcNAc modification of MR was investigated with coimmunoprecipitation assays. We mapped actual O-GlcNAc sites on MR by liquid chromatography-tandem mass spectrometry and generated several MR mutants. 3) We evaluated the expression levels of MR and the total O-GlcNAc levels in kidneys of 9-week-old db/db mice. We also intraperitoneally administered 3 g/kg DON to them for five days and evaluated the same subjects.Results: 1) Treatments with either 30 mM glucose or PUGNAc enhanced 10–10 M aldosterone-mediated MR transactivation by 2-fold and increased endogenous SGK1 mRNA levels. These changes were accompanied by increased expression levels of MR protein. In contrast, treatment with DON lowered a reporter activity and the expression levels of MR. 2) Coimmunoprecipitation assays showed that MR was modified by O-GlcNAc and this modification of MR was increased by 30 mM glucose and PUGNAc treatment. The MR mutant of multiple O-GlcNAc sites (S295A/S296A/S298A/S299A) showed the decrease of its O-GlcNAc level, which was accompanied by lowering their expression levels and transcriptional activities by 40%. 3) The levels of MR protein increased by 2.5-fold in parallel with O-GlcNAc levels in kidneys of db/db mice. In addition, mRNA levels of SGK1 increased by 2-fold in db/db mice. Conversely, administration of DON decreased the expression levels of MR parallel to the total O-GlcNAc levels in kidneys. Conclusions: We showed for the first time that MR is a target for O-GlcNAc modification. High glucose conditions enhance O-GlcNAc modification of MR, which are associated with increased MR levels and its transcriptional activities in vitro and in vivo. The epigenetic modification of MR may account for the pathological MR activation in diabetes mellitus." @default.
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• W4315702962 date "2023-01-01" @default.
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• W4315702962 title "PS-BPB08-7: MECHANISMS OF MINERALOCORTICOID RECEPTOR-ASSOCIATED HYPERTENSION IN DIABETES MELLITUS: ROLE OF O-GLCNAC MODIFICATION" @default.
• W4315702962 doi "https://doi.org/10.1097/01.hjh.0000915652.85340.be" @default.
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