Abstract 026: Renal Medullary (Pro)Renin Receptor Mediates Angiotensin II-Induced Hypertension via Enhancement of Local Renin Response and Renal Medullary α-ENaC Expression
(Pro)renin receptor (PRR) is predominantly expressed in the collecting duct and is stimulated by angiotensin II (AngII) via the COX-2/PGE2/EP4 pathway but the function of PRR is unknown. We examined the effect of intramedullary delivery of a novel PRR decoy peptide PRO20 on AngII hypertension via an interstitial catheter chronically placed in the rat medulla. Telemetry showed that 1-wk AngII infusion (100 ng/kg/min) elevated MAP from 108 ± 5.8 to 164.7 ± 6.2 mmHg and this value was lowered to 110.2 ± 4.8 mmHg (p<0.05) by intramedullary PRO20 infusion (IMPRO) at 120μg/kg/d but was only modestly affected by intravenous PRO20 infusion (IVPRO) (day 7: 151.7 ± 4.4 mmHg). The indices of kidney injury including proteinuria (2.7-fold increase in urinary protein), glomerulosclerosis and interstitial fibrosis following AngII infusion were completely normalized by IMPRO so were the polyuria and downregulation of renal AQP2 protein expression. AngII infusion elevated urinary renin activity from 0.17 ± 0.013 to 9.3 ± 1.7 AngI ng/24h, which was reduced to 0.09 ± 0.04 AngI ng/24h by IMPRO. A similar pattern of changes in renin activity was observed in the inner medulla, contrasting to opposite changes in renal cortex and plasma. α-ENaC mRNA and protein were elevated 158% and 180%, respectively, in the inner medulla but not in the cortex or plasma, and the elevations were abolished by IMPRO. By chopstick electrodes, amiloride-sensitive sodium transport was increased from 13.06 ± 1.2 to 115.19 ± 7.5 Ieq μA/cm2 by aldosterone, which was abolished by PRO20 (10.5 ± 3.75 Ieq μA/cm2). Together, these results suggest that renal medullary PRR determines the hypertension likely via mediating the local renin response and the direct activation of ENaC during AngII infusion.
Author Disclosures: F. Wang: None. X. Lu: None. Y. Feng: None. T. Yang: None.
- © 2014 by American Heart Association, Inc.