Abstract 602: RAS-induced Hypertension Is Primarily Mediated By (Pro)renin Receptor Activation At The Paraventricular Nucleus Of The Hypothalamus.
Studies have shown that renin-angiotensin-system (RAS)-induced inflammation at the paraventricular nucleus of the hypothalamus (PVN) contributes to hypertension development by increasing sympathetic outflow and elevating blood pressure. Recent data suggest that PRR activation increases pro-inflammatory cytokine (PIC) production in an Ang II-independent manner helping sustain kidney inflammation, retinal disease and diabetic neuropathy. Astrocytes house all the components of the RAS and help regulate the immune response within the brain. However, the role of (pro)renin (PRO) receptor (PRR) activation at the PVN on blood pressure regulation and astrocyte activation has not been evaluated. We show that at the PVN, 12 weeks old spontaneously hypertensive rats (SHRs) have significantly (p < 0.05) higher PRR mRNA levels than normotensive Wistar Kyoto (WKY) and Sprague Dawley (SD) rats (1.6 ± 0.3 vs. 0.96 ± 0.4 & 1.0 ± 0.2, SHR, WKY and SD respectively). In situ-hybridization data using RNA Scope, confirmed these results as qualitative analysis from coronal sections containing the PVN from SD and WKY rats showed lower PRR signal when compared to those from SHRs. Our data shows that bilateral downregulation of the PRR, using a short-hairpin RNA (shRNA) vector construct, at the PVN of SHRs (n = 5) reduces blood pressure compared to control animals (n = 5) with PRR levels intact (146.1 ± 6.6 vs. 133.3 ± 9.0 mmHG; p < 0.05). Similarly, PRR downregulation at the PVN can also reduce the pressor response triggered by sub-cutaneous Ang II infusion (200ng/kg/min) in SD rats (143 ± 13.2 vs. 114.8 ± 13.2 mmHG, p < 0.05; control vs. shRNA animals, respectively). In both experimental designs, blood pressure decreases were not accompanied by changes in heart rate. Our results also show lower glial fibrillary acidic protein (GFAP) and interleukin (IL)-1β mRNA levels at the PVN in shRNA-injected animals and using the Image J tool we show a trend for astroglial area fraction in the PVN to decrease. These changes are in concert with our in vitro data which show that PRO increases PICs levels and astrogliosis in cultured astrocytes. Our findings show that at the PVN, PRR activation is key in RAS-induced hypertension and potential mechanisms may include astrocyte- and neuroimmune activation.
Author Disclosures: V. Rodríguez: None. A.D. de Kloet: None. T.S. Chan: None. C. Sumners: None.
- © 2014 by American Heart Association, Inc.