Knockdown of mineralocorticoid or angiotensin II type 1 receptor gene expression in the paraventricular nucleus prevents angiotensin II hypertension in rats. (22nd July 2014)

• Record Type: Journal Article
• Authors: Chen, Aidong; Huang, Bing S.; Wang, Hong‐Wei; Ahmad, Monir; Leenen, Frans H. H.
• Is Part Of: Journal of physiology. Volume 592:Number 16(2014:Aug.)
• Page Start: 3523
• Page End: 3536
• Publication Date: 2014-07-22
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2014.275560
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="tjp6261-sec-0010" sec-type="section"> <title>Key points</title> <p> <list id="tjp6261-list-0001" list-type="bullet"> <list-item> <p>Chronic subcutaneous infusion of Ang II causes a progressive increase in blood pressure (BP) associated with significant increases in angiotensin type 1 receptor (AT<sub>1</sub>R) and mineralocorticoid receptor (MR) expression in hypothalamic nuclei.</p> </list-item> <list-item> <p>Intra‐paraventricular nucleus (PVN) infusion of AAV‐ AT<sub>1a</sub>R‐siRNA or of AAV‐MR‐siRNA markedly knockdown AT<sub>1a</sub>‐R or MR expression in the PVN but not in the subfornical organ; or supraoptic nucleus, and prevent most of the increase in BP.</p> </list-item> <list-item> <p>These findings indicate that increased MR and AT<sub>1</sub>R activation in the PVN play a critical role in Ang II‐induced hypertension in rats on regular salt intake.</p> </list-item> </list> </p> </sec> <sec id="tjp6261-sec-0020" sec-type="section"> <title>Abstract</title> <p>Circulating Ang II activates an aldosterone‐mineralocorticoid receptor (MR) – angiotensin II (Ang II) – angiotensin type 1 receptor (AT<sub>1</sub>R) pathway in the hypothalamus. To obtain insights into the actual neuronal projections involved, adeno‐associated virus carrying small interfering RNA against either AT<sub>1a</sub>R (AAV‐AT<sub>1a</sub>R‐siRNA) or MR (AAV‐MR‐siRNA) were infused into the paraventricular nucleus (PVN) in Wistar rats. Intra‐PVN infusion of AAV‐AT<sub>1a</sub>R‐siRNA or AAV‐MR‐siRNA decreased AT<sub>1</sub>R or MR expression in the PVN but not in the subfornical organ (SFO) or supraoptic nucleus (SON). Subcutaneous infusion of Ang II at 500 ng kg<sup>−1</sup> min<sup>−1</sup> for 2 weeks increased mean arterial pressure by 60–70 mmHg, and increased AT<sub>1</sub>R and MR expression in the SFO, SON and PVN. Intra‐PVN AT<sub>1a</sub>R‐siRNA prevented the Ang II‐induced increase in AT<sub>1</sub>R but not MR expression in the PVN, and MR‐siRNA prevented MR but not AT<sub>1</sub>R expression in the PVN. The increases in AT<sub>1</sub>R and MR expression in both the SFO and the SON were not changed by the two AAV‐siRNAs. Specific knockdown of AT<sub>1</sub>R or MR in the PVN by AAV‐siRNA each prevented most of the Ang II‐induced hypertension. Prevention of the subcutaneous Ang II‐induced increase in MR but not the increase in AT<sub>1</sub>R by knockdown of MR and vice versa suggests an independent regulation of MR and AT<sub>1</sub>R expression in the PVN. Both AT<sub>1</sub>R and MR activation in the PVN play a critical role in Ang II‐induced hypertension in rats.</p> </sec> </abstract>