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

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.

The advanced glycation end-products (AGEs)/ROS/NLRP3 inflammasome axis contributes to delayed diabetic corneal wound healing and nerve regeneration

“…Moreover, using immunostaining, we also found increased oxidative stress during diabetic corneal wound closure, characterized by aggravated ROS accumulation, and elevated expression of NADPH oxidase 2 (NOX2) and NOX4 in the corneal epithelial layer (Supplementary Fig. 2), which was reported to be related to NLRP3 inflammasome activation [27]. Taken together, the findings indicated that the sustained activation of NLRP3 inflammasome probably contributed to the postponed diabetic corneal wound closure.…”

“…Combined with the overexpression of NADPH oxidase (NOX2 and NOX4) during diabetic corneal wound healing, these findings mechanistically demonstrated that the AGEgenerated ROS promoted NLRP3 inflammasome activity and inflammatory cascades, resulting in postponed diabetic corneal wound closure and impaired nerve regeneration. As previous studies supported that the ROS derived from NADPH oxidase and mitochondria both contributed to NLRP3 inflammasome activation [27,[43][44][45][46][47][48], further studies are required to determine which kind of ROS promotes AGE-induced NLRP3 inflammasome activation and delayed diabetic corneal wound healing, mitochondria-or NADPH oxidase-generated ROS.…”

Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake

“…Here, we found that chronic infusion of Elabela is more effective than Ape13 in protecting salt-loaded hypertensive rats from renal dysfunction, kidney hypertrophy, and remodeling. Accordingly, Elabela treatment was recently reported to preserve the glomerular structure, to prevent renal fibrosis and to block the expression of fibrosis-related genes in the kidneys of Dahl salt-sensitive rats on a high-salt diet and deoxycorticosterone acetate/salt-treated rats (Schreiber et al, 2017;Chen et al, 2020b;Xu et al, 2020). Consistently, recent clinical data have shown, in contrast to Ape13, that the decrease in serum Elabela levels is also strongly associated with deterioration of renal function and worsening stages of chronic kidney disease (Lu et al, 2020).…”

Tribulus terrestris L. protects glomerular endothelial cells via the miR155-H2AC6 interaction network in hypertensive renal injury

“…Numerous studies have shown that miRNAs are biomarkers and therapeutic targets (37)(38)(39)(40). Thus, we constructed a miRNA-mRNA interaction network to uncover the underlying molecular mechanism in hypertensive renal injury.…”