Increased apelin receptor gene expression in the subfornical organ of spontaneously hypertensive rats.

Philip R Griffiths,Anne-Marie O'Carroll,Aoife O'Carroll-Lolait,Julian F R Paton,Aarifah Bijabhai,Stephen J Lolait,Michael Bader

doi:10.1371/journal.pone.0231844

Philip R Griffiths, Anne-Marie O'Carroll + Show 5 more

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https://doi.org/10.1371/journal.pone.0231844

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Abstract

The vascular organ of the lamina terminalis, subfornical organ (SFO), and area postrema comprise the sensory circumventricular organs (CVO) which are central structures that lie outside the blood brain barrier and are thought to provide an interface between peripherally circulating signals and the brain through their projections to central autonomic structures. The SFO expresses mRNA for the G protein-coupled apelin receptor (APJ, gene name aplnr) and exogenous microinjection of the neuropeptide apelin (apln) to the SFO elicits a depressor effect. Here we investigated the expression and cellular distribution of aplnr, apln and the recently described ligand apela (apela) in the CVOs and investigated whether differences in the levels of expression of apelinergic gene transcripts in these regions might underlie the chronic elevated blood pressure seen in hypertension. We carried out multiplex in situ hybridization histochemistry on CVO tissue sections from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) controls. Confocal immunofluorescent images indicated strong aplnr expression, with lower levels of apln and modest apela expression, in the CVOs of both WKY rats and SHRs, in both neurons and glia. The expression level of aplnr transcripts was increased in the SFO of SHRs compared to WKY rats. Our data may highlight a potential dysfunction in the communication between CVOs and downstream signalling pathways in SHRs, which may contribute to its different phenotype/s.

Highlights

Apelin, a 36 amino acid peptide, originally isolated from bovine stomach extracts, exists in numerous isoforms in vivo, all of which bind to, and activate, the G protein-coupled apelin receptor (APJ; gene name aplnr) [1, 2, 3]
No difference was seen in the number of apln RNAscope dots/cell in the OVLT (1.6 [1.5–2.0] dots/cell, Fig 1G), subfornical organ (SFO) (1.6 [1.3–1.8] dots/cell, Fig 2G) or AP (1.5 [1.2–1.8] dots/cell, Fig 3G) of spontaneously hypertensive rats (SHR) compared to Wistar Kyoto (WKY) (1.6 [1.4–1.9] dots/ cell, Fig 1G; 1.5 [0.8–1.7] dots/cell, Fig 2G; 2.8 [1.4–3.0] dots/cell, Fig 3G respectively) rats
There were no differences in the percentage of cells expressing aplnr or apln in the SHR SFO compared to WKY rats (44 [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]%, Fig 2F; 50 [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]% Fig 2H, respectively vs 44 [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]%, Fig 2F; 59 [52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68]%, Fig 2H respectively) or in the SHR AP compared to WKY rats (58 [56,57,58,59,60,61,62]%, Fig 3F; 58 [52,53,54,55,56,57,58]%, Fig 3H respectively vs 64 [57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77]%, Fig 3F; 63 [53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77]%, Fig 3H respectively)

Summary

Introduction

A 36 amino acid peptide, originally isolated from bovine stomach extracts, exists in numerous isoforms in vivo, all of which bind to, and activate, the G protein-coupled apelin receptor (APJ; gene name aplnr) [1, 2, 3]. Apelin (gene name apln) and APJ are ubiquitously expressed in peripheral cells and tissues, including vascular endothelial cells [4], cardiac myocytes [5], and kidney [6], as well as in discrete central regions such as forebrain APJ and apelin expression in SHR CVOs. hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei) and lower brainstem structures (e.g. nucleus of the solitary tract (NTS), area postrema (AP)) [7], allowing for multiple roles in the central regulation of physiological systems such as cardiovascular control [8, 9], angiogenesis [10], autonomic signalling [11,12,13], neuroprotection [14], fluid homeostasis [15], and modulation of hypothalamic-pituitary-adrenal axis activity [16, 17]. Injection of apela into the cerebroventricular system is anorexigenic [23] to date, no endogenous central expression of apela has been reported [22]

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