Abstract
ObjectiveIt has not yet been fully elucidated whether cardiac tissue levels of prorenin, renin and (P)RR are activated in hypertension with a high salt intake. We hypothesized that a high salt intake activates the cardiac tissue renin angiotensin system and prorenin-(pro)renin receptor system, and damages the heart at an early stage of hypertension.MethodsWistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) received regular (normal-salt diet, 0.9%) and high-salt (8.9%) chow for 6 weeks from 6 to 12 weeks of age. The systolic blood pressure, plasma renin activity (PRA) and plasma angiotensin II concentration were measured, and the protein expressions of prorenin, (pro)renin receptor, angiotensinogen, angiotensin II AT1 receptor, ERK1/2, TGF-β, p38MAPK and HSP27 in the myocardium were investigated. The cardiac function was assessed by echocardiography, and histological analysis of the myocardium was performed.ResultsThe high-salt diet significantly increased the systolic blood pressure, and significantly reduced the PRA and plasma angiotensin II concentration both in the WKYs and SHRs. Cardiac expressions of prorenin, renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p-p38MAPK, TGF-β and p-HSP27 were significantly increased by the high salt diet both in the WKYs and SHRs. The high-salt diet significantly increased the interventricular septum thickness and cardiomyocyte size, and accelerated cardiac interstitial and perivascular fibrosis both in the WKYs and SHRs. On the other hand, dilatation of left ventricular end-diastolic dimension and impairment of left ventricular fractional shortening was shown only in salt loaded SHRs.ConclusionThe high-salt diet markedly accelerated cardiac damage through the stimulation of cardiac (P)RR and angiotensin II AT1 receptor by increasing tissue prorenin, renin and angiotensinogen and the activation of ERK1/2, TGF-β, p38MAPK and HSP27 under higher blood pressure.
Highlights
The renin angiotensin (RA) system is a major regulator of the blood pressure [1] and has been considered to be involved in the development and progression of hypertensive heart disease [2]
Renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p-p38MAPK, transforming growth factor (TGF)-β and p-HSP27 were significantly increased by the high salt diet both in the Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR)
The body weight was significantly lighter in the SHR + high-salt (SHR+HS) group (214 ± 3 g) than in the WKY + normal-salt (WKY+NS) group (323 ± 2 g) (p < 0.001), WKY + high-salt (WKY+HS) group (314 ± 2 g) (p < 0.001) and SHR + normal-salt (SHR+NS) group (307 ± 1 g) (p < 0.001)
Summary
The renin angiotensin (RA) system is a major regulator of the blood pressure [1] and has been considered to be involved in the development and progression of hypertensive heart disease [2]. Renin and its precursor prorenin are usually produced from granular cells of the juxtaglomerular apparatus in the terminal afferent arteriole in the kidney [3]. The renal tubular segment, including the collecting duct, has been reported to be a source of prorenin [4]. Renin and prorenin bind to the (pro)renin receptor ((P)RR). Binding of prorenin to the (P)RR has been reported to be involved in the development of diabetic nephropathy [5]. It was reported that the blockade of prorenin reduced the left ventricular mass and improved the left ventricular function in spontaneously hypertensive rats (SHRs) with cardiovascular damage due to excess salt, suggesting the involvement of prorenin in cardiac damage [6]
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