Mechanisms of mineralocorticoid receptor-associated hypertension in diabetes mellitus: the role of O-GlcNAc modification

Rie Jo, Hirotaka Shibata, Isao Kurihara, Kenichi Yokota, Sakiko Kobayashi, Ayano Murai-Takeda, Yuko Mitsuishi, Takeshi Hayashi, Toshifumi Nakamura, Hiroshi Itoh

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
JournalHypertension Research
DOIs
Publication statusAccepted/In press - 2022

Keywords

  • Diabetes mellitus
  • Diabetic nephropathy
  • Hypertension
  • Mineralocorticoid receptor
  • O-linked N-acetylglucosamine

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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