TY - JOUR
T1 - High glucose stimulates mineralocorticoid receptor transcriptional activity through the protein kinase C β signaling
AU - Hayashi, Takeshi
AU - Shibata, Hirotaka
AU - Kurihara, Isao
AU - Yokota, Kenichi
AU - Mitsuishi, Yuko
AU - Ohashi, Kennosuke
AU - Murai-Takeda, Ayano
AU - Jo, Rie
AU - Ohyama, Takako
AU - Sakamoto, Masaya
AU - Tojo, Katsuyoshi
AU - Tajima, Naoko
AU - Utsunomiya, Kazunori
AU - Itoh, Hiroshi
N1 - Funding Information:
From the 1Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 2Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo and 3Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Japan. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (to H.S., I.K. and R.J.), Keio Gi-juku Fukuzawa Memorial Fund for the Advancement of Education and Research (to H.S. and I.K.), and grant from the Smoking Research Foundation (to H.I. and H.S.). Address for correspondence: Hirotaka Shibata, MD, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan. E-mail: hiro-405@cb3.so-net.ne.jp Received for publication December 27, 2016. Revised and accepted January 5, 2017. Released in advance online on J-STAGE September 30, 2017. doi: 10.1536/ihj.16-649 All rights reserved by the International Heart Journal Association.
Publisher Copyright:
© 2017, International Heart Journal Association. All rights reserved.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
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.
KW - Diabetes mellitus
KW - Diabetic complication
KW - Resistant hypertension
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U2 - 10.1536/ihj.16-649
DO - 10.1536/ihj.16-649
M3 - Article
C2 - 28966330
AN - SCOPUS:85032179529
SN - 1349-2365
VL - 58
SP - 794
EP - 802
JO - International Heart Journal
JF - International Heart Journal
IS - 5
ER -
