PMID- 28604611
OWN - NLM
STAT- MEDLINE
DCOM- 20180402
LR  - 20181202
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 18
IP  - 6
DP  - 2017 Jun 11
TI  - Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice.
LID - 10.3390/ijms18061250 [doi]
LID - 1250
AB  - The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid 
      and electrolyte homeostasis and is located in the aldosterone-sensitive distal 
      nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed 
      salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in 
      ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone 
      blocker, is a promising therapeutic option for resistant or/and salt-sensitive 
      hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to 
      blood pressure, metabolic parameters, and molecular level changes in ASDN under 
      high oral salt intake. We found that EPL failed to reduce blood pressure in KO 
      mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, 
      salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression 
      analyses of laser-captured specimens in ASDN suggested the presence of 
      non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 
      KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 
      KO mice suggest that enhanced ENaC gene expression is critically involved in 
      salt-sensitive hypertension under certain conditions of specific enzyme isoforms 
      for their ubiquitination.
FAU - Kino, Tabito
AU  - Kino T
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. kino-tabito@umin.ac.jp.
FAU - Ishigami, Tomoaki
AU  - Ishigami T
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. tommmish@yokohama-cu.ac.jp.
FAU - Murata, Tsumugi
AU  - Murata T
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. e123080g@yokohama-cu.ac.jp.
FAU - Doi, Hiroshi
AU  - Doi H
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. t156052b@yokohama-cu.ac.jp.
FAU - Nakashima-Sasaki, Rie
AU  - Nakashima-Sasaki R
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. musika0720@yahoo.co.jp.
FAU - Chen, Lin
AU  - Chen L
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. mysterylin@foxmail.com.
FAU - Sugiyama, Michiko
AU  - Sugiyama M
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. vn_nv2525smile@yahoo.co.jp.
FAU - Azushima, Kengo
AU  - Azushima K
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. azushima@yokohama-cu.ac.jp.
AD  - Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 
      College Road, Singapore 169857, Singapore. azushima@yokohama-cu.ac.jp.
FAU - Wakui, Hiromichi
AU  - Wakui H
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. hiro1234@yokohama-cu.ac.jp.
FAU - Minegishi, Shintaro
AU  - Minegishi S
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. shintaro.minegish@gmail.com.
FAU - Tamura, Kouichi
AU  - Tamura K
AD  - Department of Medical Science and Cardiorenal Medicine, Graduate School of 
      Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, 
      Japan. tamukou@yokohama-cu.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20170611
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Epithelial Sodium Channels)
RN  - 0 (Sodium Chloride, Dietary)
RN  - 27O7W4T232 (Spironolactone)
RN  - 6995V82D0B (Eplerenone)
RN  - EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases)
RN  - EC 2.3.2.26 (Nedd4l protein, mouse)
SB  - IM
MH  - Animals
MH  - Blood Pressure/drug effects
MH  - Epithelial Sodium Channels/*drug effects/genetics
MH  - Eplerenone
MH  - Gene Expression Regulation
MH  - Gene Knockout Techniques
MH  - Hypertension/*drug therapy/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Nedd4 Ubiquitin Protein Ligases/*genetics
MH  - Sodium Chloride, Dietary/pharmacology
MH  - Spironolactone/*analogs & derivatives/pharmacology
PMC - PMC5486073
OTO - NOTNLM
OT  - Nedd4-2 C2
OT  - amiloride
OT  - eplerenone
OT  - hypertension
OT  - resistant hypertension
OT  - salt sensitivity
COIS- The authors declare no conflict of interest.
EDAT- 2017/06/13 06:00
MHDA- 2018/04/03 06:00
PMCR- 2017/06/01
CRDT- 2017/06/13 06:00
PHST- 2017/01/29 00:00 [received]
PHST- 2017/05/29 00:00 [revised]
PHST- 2017/06/07 00:00 [accepted]
PHST- 2017/06/13 06:00 [entrez]
PHST- 2017/06/13 06:00 [pubmed]
PHST- 2018/04/03 06:00 [medline]
PHST- 2017/06/01 00:00 [pmc-release]
AID - ijms18061250 [pii]
AID - ijms-18-01250 [pii]
AID - 10.3390/ijms18061250 [doi]
PST - epublish
SO  - Int J Mol Sci. 2017 Jun 11;18(6):1250. doi: 10.3390/ijms18061250.