Alamandine alleviates hypertension and renal damage via oxidative-stress attenuation in Dahl rats

Juexiao Gong,Shan Zhong,Man Luo,Yonghong Yong,Peng Li

doi:10.1038/s41420-022-00822-y

Abstract

Alamandine (Ala) is a novel member of the renin–angiotensin-system (RAS) family. The present study aimed to explore the effects of Ala on hypertension and renal damage of Dahl salt-sensitive (SS) rats high-salt diet-induced, and the mechanisms of Ala on renal-damage alleviation. Dahl rats were fed with high-salt diets to induce hypertension and renal damage in vivo, and HK-2 cells were treated with sodium chloride (NaCl) to induce renal injury in vitro. Ala administration alleviated the high-salt diet-induced hypertension, renal dysfunction, and renal fibrosis and apoptosis in Dahl SS rats. The HK-2 cells’ damage, and the increases in the levels of cleaved (c)-caspase3, c-caspase8, and c-poly(ADP-ribose) polymerase (PARP) induced by NaCl were inhibited by Ala. Ala attenuated the NaCl-induced oxidative stress in the kidney and HK-2 cells. DETC, an inhibitor of SOD, reversed the inhibitory effect of Ala on the apoptosis of HK-2 cells induced by NaCl. The NaCl-induced increase in the PKC level was suppressed by Ala in HK-2 cells. Notably, PKC overexpression reversed the moderating effects of Ala on the NaCl-induced apoptosis of HK-2 cells. These results show that Ala alleviates high-salt diet-induced hypertension and renal dysfunction. Ala attenuates the renal damage via inhibiting the PKC/reactive oxygen species (ROS) signaling pathway, thereby suppressing the apoptosis in renal tubular cells.

Highlights

Hypertension is the most prevalent cardiovascular disease and the major risk factor for the high morbidity and mortality of chronic disease, which have caused overwhelming global economic and health problems [1]
Ala alleviated high-salt diet-induced renal dysfunction and hypertension of Dahl SS rats The levels of blood urea nitrogen (BUN), Cr, and cystatin C (CysC) were higher in Dahl SS rats than in vectors harboring PKC (Ad-PKC; GeneChem, Shanghai, China) were concurrently added to the NaCl + Ala + Ad-PKC and NaCl + Ala cultures
Medium dose (500 μg/kg/d) or high dose (5000 μg/kg/d), but not the low dose (50 μg/kg/d) of Ala attenuated the increases in BUN, Cr, and CysC in the Dahl SS rats subjected to high-salt diet

Summary

Introduction

Hypertension is the most prevalent cardiovascular disease and the major risk factor for the high morbidity and mortality of chronic disease, which have caused overwhelming global economic and health problems [1]. High-salt intake is a risk factor for hypertension, stroke, and cardiovascular diseases [2]. A relationship exists between dietary salt intake and hypertension [3]. The positive correlation relationship between dietary salt intake and high blood pressure has been well described, the precise mechanisms of saltinduced hypertension are still poorly understood. Refractory hypertension is common in chronic kidney-disease patients and conveys an increased risk for adverse cardiovascular outcomes and the development of renal failure [4]. Sodium chloride (NaCl) diets were found to cause interstitial fibrosis, tubular dilatation, glomerular sclerosis, and tubular epithelial-cell apoptosis in rats [6, 7]

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