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Int. J. Mol. Sci. 2017, 18(6), 1250; doi:10.3390/ijms18061250

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

1
Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
2
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
*
Author to whom correspondence should be addressed.
Academic Editors: Anastasia Susie Mihailidou, Jan Danser, Sadayoshi Ito, Fumitoshi Satoh and Akira Nishiyama
Received: 29 January 2017 / Revised: 29 May 2017 / Accepted: 7 June 2017 / Published: 11 June 2017
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Abstract

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. View Full-Text
Keywords: salt sensitivity; hypertension; Nedd4-2 C2; eplerenone; amiloride; resistant hypertension salt sensitivity; hypertension; Nedd4-2 C2; eplerenone; amiloride; resistant hypertension
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MDPI and ACS Style

Kino, T.; Ishigami, T.; Murata, T.; Doi, H.; Nakashima-Sasaki, R.; Chen, L.; Sugiyama, M.; Azushima, K.; Wakui, H.; Minegishi, S.; Tamura, K. Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice. Int. J. Mol. Sci. 2017, 18, 1250.

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