Abstract
Background(Pro)renin receptor (PRR) is a new component of the renin–angiotensin system and regulates renin activity in vitro. Within the kidney, PRR is highly expressed in the renal medulla where its expression is induced by angiotensin II infusion. The objective of the present study was to test a potential role of renal medullary PRR during angiotensin II-induced hypertension.MethodsA rat AngII infusion model (100 ng/kg/min) combined with renal intramedullary infusion of PRO20, a specific inhibitor of PRR, was builded. And the intravenous PRO20 infusion serve as control. Mean arterial pressure was recorded by radiotelemetry for one week. Further anaylsis of kidney injury, inflammation, biochemical indices and protein localization were perrformed in vivo or in vitro.ResultsRadiotelemetry demonstrated that AngII infusion elevated the mean arteria pressure from 108 ± 5.8 to 164.7 ± 6.2 mmHg. Mean arterial pressure decreased to 128.6 ± 5.8 mmHg (P < 0.05) after intramedullary infusion of PRO20, but was only modestly affected by intravenous PRO20 infusion. Indices of kidney injury, including proteinuria, glomerulosclerosis, and interstitial fibrosis, inflammation, and increased renal medullary and urinary renin activity following angiotensin II infusion were all remarkably attenuated by intramedullary PRO20 infusion. Following one week of angiotensin II infusion, increased PRR immunoreactivity was found in vascular smooth muscle cells. In cultured rat vascular smooth muscle cells, angiotensin II induced parallel increases in soluble PRR and renin activity, and the latter was significantly reduced by PRO20.ConclusionRenal medullary PRR mediates angiotensin II-induced hypertension, likely by amplifying the local renin response.
Highlights
The renin–angiotensin system (RAS) is one of the most important regulatory systems for the control of extracellular volume and blood pressure (BP)
A catheter was chronically implanted in the renal medulla of nephrectomized rats to achieve sitespecific delivery of PRO20, and intravenous infusion of this peptide via the jugular vein served as a control for spillover
Consistent with the BP data, Angiotensin II (AngII)-induced cardiac hypertrophy was blunted by IM PRO20 but not IV PRO20 (Fig. 1b)
Summary
The renin–angiotensin system (RAS) is one of the most important regulatory systems for the control of extracellular volume and blood pressure (BP). (Pro)renin receptor (PRR) was cloned as a specific receptor for prorenin and renin by Nguyen et al in 2002 [8]. It is a 350-amino-acid protein containing a single transmembrane domain [9]. In vitro evidence demonstrates that prorenin bound to PRR has increased catalytic activity, mediating local AngII formation [8, 12]. Apart from prorenin or renin activation, activation of PRR by (pro)renin stimulates a variety of signal transduction pathways such as mitogen-activated protein kinase [14] and Wnt-βcatenin pathways [15], independent of AngII [14, 15]. The present study tested the functional role of renal medullary PRR during AngII-induced hypertension
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