Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats.

Chihiro Okamoto,Hiromitsu Kanamori,Kazuhiko Nishigaki,Masanori Kawasaki,Shinya Minatoguchi,Takuma Aoyama,Yoshihisa Yamada,Shingo Minatoguchi,Yuka Hayakawa,Masamitsu Iwasa,Hisaaki Komaki,Atsushi Mikami,Michael Bader

doi:10.1371/journal.pone.0189099

Abstract

ObjectiveA high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart.MethodsWistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated.ResultsThe excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs.ConclusionAn excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

Highlights

It has been reported that excessive salt intake increases the blood pressure and the restriction of salt intake decreases blood pressure [1]
The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) but the extent was greater in SHRs
We previously reported that a high salt intake enhanced cardiac expressions of prorenin, renin, andrenin receptor [(P)RR] as well as cardiac angiotensinogen and angiotensin II AT1 receptor, and activated their downstream signals ERK1/2, transforming growth factor (TGF)-β1, p38 mitogen-activated protein kinase (p38MAPK), and HSP27, leading to the acceleration of cardiac interstitial fibrosis, perivascular fibrosis, and cardiomyocyte hypertrophy and to the deterioration of the cardiac function in spontaneously hypertensive rats (SHRs) [3]

Summary

Introduction

It has been reported that excessive salt intake increases the blood pressure and the restriction of salt intake decreases blood pressure [1]. It has recently been reported that large-scale prospective cohort clinical trials demonstrated that subjects with a low salt diet were associated with higher rates of cardiovascular disease morbidity and mortality compared with those with a normal or high salt diet [7, 8]. At first glance, these results are confusing because they are different from the common sense view that a high salt intake is associated with an increased risk of cardiovascular disease [2]. It has been reported that a low salt diet was associated with the sympathetic nervous system in patients with hypertension [12]

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Results

Conclusion