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

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.

Long-term low salt diet increases blood pressure by activation of the renin-angiotensin and sympathetic nervous systems

“…The increased renal expression of AT 1 R may be associated with increased renal AT 1 R function because the intrarenal infusion of the AT 1 R antagonist candesartan increased urine flow and sodium excretion to a greater extent in the SD rats fed low than normal salt diet. Thus, the low salt diet may have increased the blood pressure by an overactivation of the RAS, similar to that proposed in some (14,37,44,45) but not in other studies (16). The sympathetic nervous system also plays an important role in the pathogenesis of hypertension (46)(47)(48).…”

“…Nicolantonio R, et al reported that low salt diet (0.1% NaCl from weaning until 6 months of age) attenuated the development of hypertension and increased mortality rate in the SHR, but not altered the blood pressure of normotensive WKY rats (52). The low salt (0.01% salt diet for 8 weeks) diet did not affect the systolic blood pressure but increased the heart rate both in WKYs and SHRs (37). Systolic blood pressure was lower and heart rate was higher in male Wistar rats fed a low salt diet (0.06% Na) from weaning to adulthood (53).…”

“…Moreover, the inconsistent effects of low salt intake on blood pressure have also been reported in animal studies. A decrease in salt intake has been reported to decrease the blood pressure of SHRs (17) but tended to increase the blood pressure in normotensive rats (16) while other studies have found no effect of low salt diet on blood pressure in SHRs and humans (36,37). The reasons for the different results of low salt intake on blood pressure are not clear but may include the varying definitions of low salt diet, different animal models, and the duration of low salt feeding.…”

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

“…50 Similarly, very low salt intake (0.01% sodium) in rats increased cardiac expression of prorenin/renin and the PRR and accelerated cardiac and perivascular fibrosis despite normal blood pressure. 51 The in vivo role of cardiac PRR in hypertension and cardiac function has been difficult to determine because, as previously mentioned, constitutive deletion of the PRR in the cardiomyocytes leads to lethal heart failure as a result of impaired lysosomal function. 15 Global or cardiospecific overexpression of the PRR did not alter BP or cardiac structure or function at baseline 46,48 or in response to stress and ischemic injury.…”

(Pro)renin Receptor is Involved in Myocardial Damage in Alcoholic Cardiomyopathy

“…In addition to the function of Ang II, a series of intracellular signaling pathways is directly activated due to this binding. In spontaneously hypertensive rats, PRR aggravates myocardial fibrosis and cardiac hypertrophy by activating the MAPK superfamily (Okamoto et al., ). In cardiomyoblasts (H9C2 cell lines), silencing PRR significantly decreases p38 phosphorylation and the hypoxia/reoxygenation‐induced apoptosis (Liu et al., ).…”