Expression and functional implications of the renal apelinergic system in rodents

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.