Angiotensin-(1–7) in Paraventricular Nucleus Modulates Sympathetic Activity and Cardiac Sympathetic Afferent Reflex in Renovascular Hypertensive Rats

Han, Ying; Sun, Hai-Jian; Gao, Qing; Zhou, Ye-Bo; Zhang, Feng; Gao, Xing-Ya; Zhu, Guo‐Qing

doi:10.1371/journal.pone.0048966

Cited by 31 publications

(26 citation statements)

References 52 publications

(69 reference statements)

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“…Beside the work by Tallant and Clark 21 and by Liu et al 22 in primary cells, an article from 2012 showed indirect cAMP involvement in Ang-(1-7) signaling because its modulation of sympathetic activity in the paraventricular nucleus was abolished by an AC inhibitor and a PKA inhibitor. 31 Furthermore, physiological effects of the heptapeptide and effects in preclinical models also implicate the involvement of cAMP. For example, we demonstrated the dominant effect of Ang-(1-7) on hematopoietic stem cells/progenitors, 32 and there is a significant evidence that cAMP stimulates such processes.…”

Section: Discussionmentioning

confidence: 99%

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

et al. 2016

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Angiotensin (Ang)-(1–7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin–angiotensin system. Although it is well accepted that the G-protein–coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang-(1–7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1–7) allowing confirmation as well as discovery of the heptapeptide’s receptors. Ang-(1–7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1–7). Moreover, we identified the G-protein–coupled receptor MrgD as a second receptor for Ang-(1–7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in both Mas and MrgD . Mice deficient in MrgD showed an impaired hemodynamic response after Ang-(1–7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin–angiotensin system, by identifying a second receptor for Ang-(1–7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319.

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Section: Discussionmentioning

confidence: 99%

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

et al. 2016

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“…More recently, A-779 injections into the PVN have been shown to attenuate hypertension induced by a sleep apnea model in rats (108), which agrees with the sympathetic stimulatory effect of acute injections of ANG-(1-7) into the PVN. Nevertheless, ANG-(1-7) injections into the PVN effectively increased the RSNA, CSAR, and arterial pressure through an activation of MAS via the cAMP-PKA pathway (237,307,308,527,640). However, these studies were performed in anesthetized vagotomized and sinoaortic denervated rats, a condition that may introduce important changes in the activity of PVN neurons and their sensitivity to neuromodulators.…”

Section: Cardiovascular Effects Of Angiotensin-(1-7) At Specific Hypomentioning

confidence: 99%

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

Santos

Sampaio

Alzamora

et al. 2018

Physiological Reviews

863

906

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The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.

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“…This AAR has been extended recently to other WAT pads, but with renal sympathetic nerve activity increases (adipose afferent renal reflex, AARR) with related changes in blood pressure and other cardiovascular responses (19,22,35,42,55,66,67).…”

Section: R896mentioning

confidence: 99%

Short and long sympathetic-sensory feedback loops in white fat

Ryu

Bartness

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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We previously demonstrated white adipose tissue (WAT) innervation using the established WAT retrograde sympathetic nervous system (SNS)-specific transneuronal viral tract tracer pseudorabies virus (PRV152) and showed its role in the control of lipolysis. Conversely, we demonstrated WAT sensory innervation using the established anterograde sensory system (SS)-specific transneuronal viral tracer, the H129 strain of herpes simplex virus-1, with sensory nerves showing responsiveness with increases in WAT SNS drive. Several brain areas were part of the SNS outflow to and SS inflow from WAT between these studies suggesting SNS-SS feedback loops. Therefore, we injected both PRV152 and H129 into inguinal WAT (IWAT) of Siberian hamsters. Animals were perfused on days 5 and 6 postinoculation after H129 and PRV152 injections, respectively, and brains, spinal cords, sympathetic, and dorsal root ganglia (DRG) were processed for immunohistochemical detection of each virus across the neuroaxis. The presence of H129ϩPRV152-colocalized neurons (ϳ50%) in the spinal segments innervating IWAT suggested short SNS-SS loops with significant coinfections (Ͼ60%) in discrete brain regions, signifying long SNS-SS loops. Notably, the most highly populated sites with the double-infected neurons were the medial part of medial preoptic nucleus, medial preoptic area, hypothalamic paraventricular nucleus, lateral hypothalamus, periaqueductal gray, oral part of the pontine reticular nucleus, and the nucleus of the solitary tract. Collectively, these results strongly indicate the neuroanatomical reality of the central SNS-SS feedback loops with short loops in the spinal cord and long loops in the brain, both likely involved in the control of lipolysis or other WAT pad-specific functions.herpes simplex virus; pseudorabies virus; Siberian hamsters; sympathetic nervous system; sensory system; white adipose tissue WE PREVIOUSLY DEMONSTRATED postganglionic sympathetic nervous system (SNS) innervation of inguinal and epididymal white adipose tissue [IWAT and EWAT, respectively;(69)] and together with others determined that the pattern of SNS drive is fat pad-specific (15,29,43). Collectively, these and other data such as the blockade of lipolysis with WAT SNS denervation (for review see Refs. 8 and 9) establish that activation of the SNS innervation of WAT is the principal mechanism underlying lipid mobilization. To unravel the central nervous system (CNS) origins controlling the sympathetic drive to WAT, we used the retrograde transneuronal tract tracer pseudorabies virus (PRV) Bartha's K strain to define the CNS origins of the sympathetic outflow to IWAT and EWAT in Siberian hamsters as well as in Sprague-Dawley rats (4). We and others expanded these studies not only for subcutaneous WAT and the retroperitoneal WAT (RWAT) depot (1, 13, 52, 57) but also for true visceral WAT (mesenteric WAT; see Ref. 46). It is noteworthy that the SNS components responsible for sympathetic outflow to the aforementioned fat pads share many central sites in the circuit...

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Angiotensin-(1–7) in Paraventricular Nucleus Modulates Sympathetic Activity and Cardiac Sympathetic Afferent Reflex in Renovascular Hypertensive Rats

Cited by 31 publications

References 52 publications

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

Short and long sympathetic-sensory feedback loops in white fat

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