High glucose stimulates mineralocorticoid receptor transcriptional activity through the protein kinase C β signaling

Takeshi Hayashi, Hirotaka Shibata, Isao Kurihara, Kenichi Yokota, Yuko Mitsuishi, Kennosuke Ohashi, Ayano Takeda, Rie Jo, Takako Ohyama, Masaya Sakamoto, Katsuyoshi Tojo, Naoko Tajima, Kazunori Utsunomiya, Hiroshi Itoh

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCβ by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCβ but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCβ by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCβ2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCβ signaling, which leads to MR stabilization and its transcriptional activities.

Original languageEnglish
Pages (from-to)794-802
Number of pages9
JournalInternational Heart Journal
Volume58
Issue number5
DOIs
Publication statusPublished - 2017 Sep 1

Fingerprint

Mineralocorticoid Receptors
Protein Kinase C
Glucose
Proteins
Protein C Inhibitor
Ubiquitination
Tetradecanoylphorbol Acetate
Diabetes Complications
Protein Kinase Inhibitors
Small Interfering RNA
Diabetes Mellitus
Hypertension
Kidney

Keywords

  • Diabetes mellitus
  • Diabetic complication
  • Resistant hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

High glucose stimulates mineralocorticoid receptor transcriptional activity through the protein kinase C β signaling. / Hayashi, Takeshi; Shibata, Hirotaka; Kurihara, Isao; Yokota, Kenichi; Mitsuishi, Yuko; Ohashi, Kennosuke; Takeda, Ayano; Jo, Rie; Ohyama, Takako; Sakamoto, Masaya; Tojo, Katsuyoshi; Tajima, Naoko; Utsunomiya, Kazunori; Itoh, Hiroshi.

In: International Heart Journal, Vol. 58, No. 5, 01.09.2017, p. 794-802.

Research output: Contribution to journalArticle

Hayashi, Takeshi ; Shibata, Hirotaka ; Kurihara, Isao ; Yokota, Kenichi ; Mitsuishi, Yuko ; Ohashi, Kennosuke ; Takeda, Ayano ; Jo, Rie ; Ohyama, Takako ; Sakamoto, Masaya ; Tojo, Katsuyoshi ; Tajima, Naoko ; Utsunomiya, Kazunori ; Itoh, Hiroshi. / High glucose stimulates mineralocorticoid receptor transcriptional activity through the protein kinase C β signaling. In: International Heart Journal. 2017 ; Vol. 58, No. 5. pp. 794-802.
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AU - Mitsuishi, Yuko

AU - Ohashi, Kennosuke

AU - Takeda, Ayano

AU - Jo, Rie

AU - Ohyama, Takako

AU - Sakamoto, Masaya

AU - Tojo, Katsuyoshi

AU - Tajima, Naoko

AU - Utsunomiya, Kazunori

AU - Itoh, Hiroshi

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AB - Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCβ by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCβ but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCβ by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCβ2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCβ signaling, which leads to MR stabilization and its transcriptional activities.

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