Abstract
Abstract only
Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na
+
and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA, also known as Toddler/Apela), a novel endogenous ligand of APJ receptor (also known as APLNR) in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of fPRR (by 31.6%), soluble PRR (sPRR) (by 46.5%), and prorenin (by 45.7%) protein expression as assessed by immunoblotting, and medium sPRR (by 66.7%) and prorenin/renin (by 60%) levels by ELISA. Conversely, deletion of PRR in the CD in mice elevated ELA mRNA levels (1.5-fold), and urinary ELA excretion (2.0-fold), supporting the antagonistic relationship between the two systems. Administration of exogenous ELA (5 mg/kg/day, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure (113.0 ± 1.7
vs
. 133.8 ± 1.5 mmHg,
P
<0.001), systolic blood pressure (BP) (122.5 ± 1.8
vs
. 142.9 ± 2.6 mmHg,
P
<0.01), diastolic BP (105.8 ± 2.3
vs
. 127.4 ± 0.9 mmHg,
P
<0.001), heart rate (347.4 ± 4.9
vs
. 394.1 ± 5.3 bpm,
P
<0.001), and albuminuria (11.4 ± 1.0
vs
. 5.1 ± 1.1 mg/24h,
P
<0.01), accompanied with a reduction of urinary sPRR (by 53.3%), Ang II (by 54.6%), prorenin/renin (by 68.7%), neutrophil gelatinase-associated lipocalin (by 51.9%), and prostaglandin E2 (by 44.9%) excretion. HS upregulated renal medullary protein expression of fPRR (218.7%) and sPRR (172.4%) in Dahl SS rats, all of which were significantly blunted by exogenous ELA infusion (by 30-55%). Together, these results support the antagonist interaction between ELA and intrarenal RAS in the distal nephron that appears to exert a major impact on blood pressure regulation.