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

Tabito Kino,Shintaro Minegishi,Kouichi Tamura,Michiko Sugiyama,Rie Nakashima-Sasaki,Tomoaki Ishigami,Hiromichi Wakui,Tsumugi Murata,Lin Chen,Hiroshi Doi,Kengo Azushima

doi:10.3390/ijms18061250

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.

Highlights

Salt sensitivity and hypertension are major human health problems because cardiovascular morbidity and mortality due to hypertension are increasing worldwide [1,2,3]
The Nedd4-2 C2 domain is encoded by exon 2 in chromosome 18 of mice, and Nedd4-2 C2 knock out (KO) mice show salt-sensitive hypertension under high oral salt intake, as reported previously [21]
The average systolic blood pressure (SBP) was lower in WT littermates than that in Nedd4-2 C2 KO mice (107.8 ± 0.5 mmHg vs. 112.6 ± 0.7 mmHg, p < 0.001)

Summary

Introduction

Salt sensitivity and hypertension are major human health problems because cardiovascular morbidity and mortality due to hypertension are increasing worldwide [1,2,3]. Recent clinical practice guidelines for managing hypertension in various countries indicate that appropriate blood pressure lowering is necessary for reducing cardiovascular mortality [4,5,6,7]. Excessive oral salt intake in subjects with salt sensitivity results in hypertension and is thought to be involved in the pathophysiological basis of resistant hypertension [16]. Eplerenone and spironolactone are therapeutic options for subjects with resistant hypertension, suggesting that residual activation of aldosterone signaling in distal tubules is the pathophysiological basis of this condition [17,18,19,20]. We found and reported the enhancement of both epithelial sodium channel (ENaC) expression and transcription along aldosterone sensitive distal nephrnon (ASDN) despite high oral salt intake by Nedd C2 KO mice. The present study aimed to elucidate the effect of eplerenone (EPL) and amiloride in Nedd C2 KO mice, as well as the molecular mechanism underlying tubular-specific activation of ENaC in this genetically engineered model of salt-sensitive hypertension

Methods

Results

Conclusion