Azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in spontaneously hypertensive rats

Abstract

We examined whether the stimulation of the angiotensin II AT1 receptor increases the expression of the cardiac (pro)renin receptor ((P)RR) and its downstream signals and whether the blockade of the angiotensin II AT1 receptor by azilsartan decreases the expression of the cardiac (P)RR and its signaling in spontaneously hypertensive rats (SHRs) with a high-salt intake. Rats received normal-salt (0.9%) chow, high-salt (8.9%) chow, normal-salt chow with 1 mg/day of azilsartan, and high-salt chow with 1 mg/day of azilsartan from 6 to 12 weeks of age. Rats with normal-salt chow were administered 100 ng/kg/min of angiotensin II by osmotic minipump from 6 to 12 weeks of age. A high-salt diet and angiotensin II significantly increased the systolic blood pressure; overexpressed cardiac (P)RR, phosphorylated (p)-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1; enhanced cardiac interstitial and perivascular fibrosis, cardiomyocyte size, interventricular septum (IVS) thickness, and left ventricular (LV) end-diastolic dimension; and decreased LV fractional shortening. Azilsartan decreased systolic blood pressure, cardiac expressions of (P)RR, p-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1, cardiac interstitial and perivascular fibrosis, cardiomyocyte size, and LV diastolic dimension, and improved LV fractional shortening. In conclusion, azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in SHRs.

Nitric Oxide Alleviated High Salt–Induced Cardiomyocyte Apoptosis and Autophagy Independent of Blood Pressure in Rats

“…High salt intake may cause cardiac damage, as indicated by increased cardiac interstitial and perivascular fibrosis, cardiomyocyte size, interventricular septum thickness, and left ventricular (LV) end-diastolic dimension and decreased LV fractional shortening ( Komaki et al, 2018 ). Cardiac apoptosis and fibrosis were found to accelerate in rats with a high-salt diet (HSD) ( Chang et al, 2019 ).…”

Cardiovascular aspects of the (pro)renin receptor: Function and significance

“…A series of studies from the Minatoguchi group in Gifu University in Japan have reported that high-salt intake significantly increased BP and cardiac damage in SHRs. 43,44 They have demonstrated that high-salt decreased plasma renin activity and AngII concentrations in rats but activated cardiac RAS and the intracellular signaling, as characterized by enhanced cardiac expression of PRR, prorenin/renin, angiotensinogen (AGT), AT1R, pERK1/2, p-p38MAPK, TGF-β, and p-HSP27, 43 these effects were significantly attenuated by AT1R inhibitor azilsartan. 44 These results indicate that high salt may accelerate cardiac damage through AT1R, at least in part, by stimulating PRR and the downstream intracellular signals.…”

“…43,44 They have demonstrated that high-salt decreased plasma renin activity and AngII concentrations in rats but activated cardiac RAS and the intracellular signaling, as characterized by enhanced cardiac expression of PRR, prorenin/renin, angiotensinogen (AGT), AT1R, pERK1/2, p-p38MAPK, TGF-β, and p-HSP27, 43 these effects were significantly attenuated by AT1R inhibitor azilsartan. 44 These results indicate that high salt may accelerate cardiac damage through AT1R, at least in part, by stimulating PRR and the downstream intracellular signals. However, it is recommended to reduce the amount of salt in the diet and the processing time to see whether the above events can be reproduced since 8.9% NaCl treatment for 6 weeks 43,44 does not reflect the situation of human consumption.…”

“…These results indicate that high salt may accelerate cardiac damage through AT1R, at least in part, by stimulating PRR and the downstream intracellular signals. However, it is recommended to reduce the amount of salt in the diet and the processing time to see whether the above events can be reproduced since 8.9% NaCl treatment for 6 weeks 43,44 does not reflect the situation of human consumption. Another study also from the Minatoguchi group has indicated that although an excessively low‐salt diet (8 weeks) did not affect the systolic BP in Wistar Kyoto rats and SHRs, it significantly raised plasma renin activity, AngI, AngII, and aldosterone concentrations 45 .…”

Implication of endoplasmic reticulum stress and mitochondrial perturbations in remote liver injury after renal ischemia/reperfusion in rats: potential protective role of azilsartan

“…Azilsartan (AZL) is a potent antihypertensive drug acting as an AT 1 R blocker (ARB), but with a higher affinity for AT 1 R, compared to other ARBs [ 14 ]. Furthermore, AZL has marked renoprotective [ 15 ], cardioprotective [ 16 ], and neuroprotective [ 17 ] effects in numerous experimental animal models. More importantly, AZL exerts a favorable role against non-alcoholic fatty liver disease in rats [ 18 ].…”