ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway

Yuting Liu,Lei Wang,Yeyan Zhu,Mengming Huang,Zhida Chen,Qiao Qiao,Haonan Li,Chunying Wu,Huangbo Lin,Qing Zhu,Cailing Huang

doi:10.1038/s41419-020-02912-0

Abstract

ELABELA (ELA), a 32-residue hormone peptide abundantly expressed in adult kidneys, has been identified as a novel endogenous ligand for APJ/Apelin receptor. The aim of this study was to investigate the role of ELA in deoxycorticosterone acetate (DOCA)/salt-induced hypertension and further explore the underlying mechanism. In DOCA/salt-treated rats, the mRNA level of ELA greatly decreased in the renal medulla. Next, overexpression of ELA in the kidney was found to attenuate DOCA/salt-induced hypertension and renal injury, including lower blood pressure, reversed glomerular morphological damage, decreased blood urea nitrogen (BUN), and blocked the accumulation of fibrotic markers. Mechanistically, ELA overexpression inhibited renal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subsequent reactive oxygen species (ROS) production, thus resulted in the blockade of formation and activation of Nod-like receptor protein 3 (NLRP3) inflammasome. The inhibitory effects of ELA on Aldosterone-stimulated NADPH oxidase/ROS/NLRP3 inflammasome pathway were confirmed in the human renal tubular cells. Furthermore, our in vivo and in vitro results showed that the deficiency of the apelin receptor APJ did not influence the antihypertensive effect and blockage to NADPH oxidase/ROS/NLRP3 pathway of ELA. Moreover, in heterozygous ELA knockout mice (ELA+/−), the ELA deficiency remarkably accelerated the onset of DOCA/salt-induced hypertension. Our data demonstrate that ELA prevents DOCA/salt-induced hypertension by inhibiting NADPH oxidase/ROS/NLRP3 pathway in the kidney, which is APJ independent. Pharmacological targeting of ELA may serve as a novel therapeutic strategy for the treatment of hypertensive kidney disease.

Highlights

Both human and animal studies demonstrate that high level of dietary salt contributes to the development of hypertension[1]
Inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit gp91phox or O2– scavenging suppresses Nod-like receptor protein 3 (NLRP3) inflammasome activation and ameliorates renal injury[14,21]. These findings suggest that the NADPH oxidase/reactive oxygen species (ROS)/NLRP3 pathway serves as a key pathogenic mechanism of salt-sensitive hypertension
Effect of ELA overexpression on the deoxycorticosterone acetate (DOCA)/salt-induced hypertension In DOCA/salt-treated rats, the mRNA level of ELA was found around 50% lower in the renal medulla (Fig. 1a)

Summary

Introduction

Both human and animal studies demonstrate that high level of dietary salt contributes to the development of hypertension[1]. It is found that excessive salt intake leads to Official journal of the Cell Death Differentiation Association. Inflammasomes are known as upstream machineries to trigger inflammation in response to danger signals from pathogens or damaged host[7,8]. NLRP3 inflammasome has been reported to play a fundamental role in the pathogenesis of saltsensitive hypertension[4,7,11,12]. The mice with NLRP3 inflammasome deficiency failed to increase BP upon the DOCA/salt treatment[7,11]. It is known that there are several pathways to activate the NLRP3 inflammasome in response to diverse endogenous and exogenous danger signals, such as reactive oxygen species (ROS)[13,14,15]

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