TY - JOUR
T1 - Mechanisms of mineralocorticoid receptor-associated hypertension in diabetes mellitus
T2 - the role of O-GlcNAc modification
AU - Jo, Rie
AU - Shibata, Hirotaka
AU - Kurihara, Isao
AU - Yokota, Kenichi
AU - Kobayashi, Sakiko
AU - Murai-Takeda, Ayano
AU - Mitsuishi, Yuko
AU - Hayashi, Takeshi
AU - Nakamura, Toshifumi
AU - Itoh, Hiroshi
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to The Japanese Society of Hypertension.
PY - 2023/1
Y1 - 2023/1
N2 - This study investigated the mechanism underlying the beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with resistant hypertension and diabetic nephropathy by examining post-translational modification of the MR by O-linked-N-acetylglucosamine (O-GlcNAc), which is strongly associated with type 2 diabetes. Coimmunoprecipitation assays in HEK293T cells showed that MR is a target of O-GlcNAc modification (O-GlcNAcylation). The expression levels and transcriptional activities of the receptor increased in parallel with its O-GlcNAcylation under high-glucose conditions. Liquid chromatography–tandem mass spectrometry revealed O-GlcNAcylation of the MR at amino acids 295–307. Point mutations in those residues decreased O-GlcNAcylation, and both the protein levels and transcriptional activities of MR. In db/db mouse kidneys, MR protein levels increased in parallel with overall O-GlcNAc levels of the tissue, accompanied by increased SGK1 mRNA levels. The administration of 6-diazo-5-oxo-L-norleucin, an inhibitor of O-GlcNAcylation, reduced tissue O-GlcNAc levels and MR protein levels in db/db mice. Thus, our study showed that O-GlcNAcylation of the MR directly increases protein levels and transcriptional activities of the receptor under high-glucose conditions in vitro and in vivo. These findings provide a novel mechanism of MR as a target for prevention of complications associated with diabetes mellitus.
AB - This study investigated the mechanism underlying the beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with resistant hypertension and diabetic nephropathy by examining post-translational modification of the MR by O-linked-N-acetylglucosamine (O-GlcNAc), which is strongly associated with type 2 diabetes. Coimmunoprecipitation assays in HEK293T cells showed that MR is a target of O-GlcNAc modification (O-GlcNAcylation). The expression levels and transcriptional activities of the receptor increased in parallel with its O-GlcNAcylation under high-glucose conditions. Liquid chromatography–tandem mass spectrometry revealed O-GlcNAcylation of the MR at amino acids 295–307. Point mutations in those residues decreased O-GlcNAcylation, and both the protein levels and transcriptional activities of MR. In db/db mouse kidneys, MR protein levels increased in parallel with overall O-GlcNAc levels of the tissue, accompanied by increased SGK1 mRNA levels. The administration of 6-diazo-5-oxo-L-norleucin, an inhibitor of O-GlcNAcylation, reduced tissue O-GlcNAc levels and MR protein levels in db/db mice. Thus, our study showed that O-GlcNAcylation of the MR directly increases protein levels and transcriptional activities of the receptor under high-glucose conditions in vitro and in vivo. These findings provide a novel mechanism of MR as a target for prevention of complications associated with diabetes mellitus.
KW - Diabetes mellitus
KW - Diabetic nephropathy
KW - Hypertension
KW - Mineralocorticoid receptor
KW - O-linked N-acetylglucosamine
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U2 - 10.1038/s41440-022-01036-6
DO - 10.1038/s41440-022-01036-6
M3 - Article
C2 - 36229526
AN - SCOPUS:85139761582
SN - 0916-9636
VL - 46
SP - 19
EP - 31
JO - Hypertension Research
JF - Hypertension Research
IS - 1
ER -