Expression and functional implications of the renal apelinergic system in rodents

Abstract

Apelin binds to the G protein-coupled apelin receptor (APJ; gene name aplnr) to modulate diverse physiological systems including cardiovascular function, and hydromineral and metabolic balance. Recently a second endogenous ligand for APJ, named apela, has been discovered. We confirm that apela activates signal transduction pathways (ERK activation) in cells expressing the cloned rat APJ. Previous studies suggest that exogenous apela is diuretic, attributable wholly or in part to an action on renal APJ. Thus far the cellular distribution of apela in the kidney has not been reported. We have utilized in situ hybridization histochemistry to reveal strong apela labelling in the inner medulla (IM), with lower levels observed in the inner stripe of the outer medulla (ISOM), of rat and mouse kidneys. This contrasts with renal aplnr expression where the converse is apparent, with intense labelling in the ISOM (consistent with vasa recta labelling) and low-moderate hybridization in the IM, in addition to labelling of glomeruli. Apelin is found in sparsely distributed cells amongst more prevalent aplnr-labelled cells in extra-tubular regions of the medulla. This expression profile is supported by RNA-Seq data that shows that apela, but not apelin or aplnr, is highly expressed in microdissected rat kidney tubules. If endogenous tubular apela promotes diuresis in the kidney it could conceivably do this by interacting with APJ in vasculature, or via an unknown receptor in the tubules. The comparative distribution of apela, apelin and aplnr in the rodent kidney lays the foundation for future work on how the renal apelinergic system interacts.

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

“…A branched chain in situ hybridization histochemistry (ISHH) assay (RNAscope Multiplex Fluorescence Assay kit; Bio-Techne) was used as described previously [6]. Briefly, sections were post-fixed in 4% PFA (pH 7.4), dehydrated in increasing concentrations of ethanol and treated for 30 minutes with RNAscope Protease IV solution.…”

“…Sections were then incubated for 2 hours with proprietary probes, designed by Bio-Techne, for the following rat sequences: apela (GenBank Accession XM_008772035 (LOC100912649); bp147-1053; 12 Z probe pairs), apln (apelin; NM_031612; bp2-996; 20 Z probe pairs), aplnr (APJ; NM_031349; bp147-1053; 20 Z probe pairs), rbfox (NeuN; NM_00134498.2; bp16-1116; 15 Z probe pairs) and gfap (Gfap; NM_017009.2, bp1539-2534; 20 Z probe pairs). The specificity of the aplnr, apln and apela probes have been validated previously [6]. A combination of 3 probes at ratio 50:1:1 was used on any one section, as determined by the channel (C1-3) designated to each probe.…”

“…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]. 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 (e.g. hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei) and lower brainstem structures (e.g.…”

Fc-Elabela fusion protein attenuates lipopolysaccharide-induced kidney injury in mice

“…It is interesting to note that apela (the elabela gene) expression was reduced by LPS, but APJ was not in LPS-treated mice. Although both apela and APJ are highly expressed in the kidney, their expression patterns are different; apela is mostly localized to tubular structures whereas APJ and apelin are more widely distributed [ 37–39 ]. LPS appeared to selectively cause apoptosis in the tubular cells ( Figure 6 A), which may explain the significantly decrease in whole tissue apela , but not APJ and apelin .…”

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

“…Elabela and apelin‐13 differentially affect the cardiorenal axis, mainly through opposing effects on counterregulation in the vasopressinergic system, and possibly additional unknown mechanisms. Elabela is abundantly expressed in the kidney and is more effective than apelin‐13 in reducing renal dysfunction/injury . Elabela and apelin‐13 also significantly improve fluid homeostasis in experimental endotoxemia and septic shock, thus limiting hypovolemia .…”