Angiotensin type 1a receptors in the median preoptic nucleus support intermittent hypoxia-induced hypertension

Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.

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AT1a Receptor Knockdown in the Median Preoptic Nucleus Attenuates the Sustained Component of Hypertension Resulting from Chronic Intermittent Hypoxia

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.lb847 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Brent Shell ◽

Joel Little ◽

Tom Cunningham

Keyword(s):

Intermittent Hypoxia ◽

Chronic Intermittent Hypoxia ◽

Preoptic Nucleus ◽

Median Preoptic Nucleus ◽

At1a Receptor

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Chronic intermittent hypoxia increases blood pressure and expression of FosB/ΔFosB in central autonomic regions

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00830.2010 ◽

2011 ◽

Vol 301 (1) ◽

pp. R131-R139 ◽

Cited By ~ 61

Author(s):

W. David Knight ◽

Joel T. Little ◽

Flavia R. Carreno ◽

Glenn M. Toney ◽

Steven W. Mifflin ◽

...

Keyword(s):

Intermittent Hypoxia ◽

Renin Angiotensin System ◽

Brain Regions ◽

Ventrolateral Medulla ◽

Chronic Intermittent Hypoxia ◽

Preoptic Nucleus ◽

Sprague Dawley ◽

Angiotensin System ◽

Sprague Dawley Rats ◽

Obstructive Sleep

Chronic intermittent hypoxia (CIH) models repetitive bouts of arterial hypoxemia that occur in humans suffering from obstructive sleep apnea. CIH has been linked to persistent activation of arterial chemoreceptors and the renin-angiotensin system, which have been linked to chronic elevations of sympathetic nerve activity (SNA) and mean arterial pressure (MAP). Because Fos and FosB are transcription factors involved in activator protein (AP)-1 driven central nervous system neuronal adaptations, this study determined if CIH causes increased Fos or FosB staining in brain regions that regulate SNA and autonomic function. Male Sprague Dawley rats were instrumented with telemetry transmitters for continuous recording of MAP and heart rate (HR). Rats were exposed to continuous normoxia (CON) or to CIH for 8 h/day for 7 days. CIH increased MAP by 7–10 mmHg without persistently affecting HR. A separate group of rats was killed 1 day after 7 days of CIH for immunohistochemistry. CIH did not increase Fos staining in any brain region examined. Staining for FosB/ΔFosB was increased in the organum vasculosum of the lamina terminalis (CON: 9 ± 1; CIH: 34 ± 3 cells/section), subfornical organ (CON: 7 ± 2; CIH: 31 ± 3), median preoptic nucleus (CON 15 ± 1; CIH: 38 ± 3), nucleus of the solitary tract (CON: 9 ± 2; CIH: 28 ± 4), A5 (CON: 3 ± 1; CIH: 10 ± 1), and rostral ventrolateral medulla (CON: 5 ± 1; CIH: 17 ± 2). In the paraventricular nucleus, FosB/ΔFosB staining was located mainly in the dorsal and medial parvocellular subnuclei. CIH did not increase FosB/ΔFosB staining in caudal ventrolateral medulla or supraoptic nucleus. These data indicate that CIH induces an increase in FosB/ΔFosB in autonomic nuclei and suggest that AP-1 transcriptional regulation may contribute to stable adaptive changes that support chronically elevated SNA.

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Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00472.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. R245-R252 ◽

Cited By ~ 4

Author(s):

Katelynn Faulk ◽

Brent Shell ◽

T. Prashant Nedungadi ◽

J. Thomas Cunningham

Keyword(s):

Blood Pressure ◽

Sleep Apnea ◽

Angiotensin Converting Enzyme ◽

Intermittent Hypoxia ◽

Chronic Intermittent Hypoxia ◽

Converting Enzyme ◽

Preoptic Nucleus ◽

Median Preoptic Nucleus ◽

Obstructive Sleep

Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin-converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure.

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Estrogen Deficiency and Colonic Function: Surgical Menopause and Sex Differences in Angiotensin and Dopamine Receptor Interaction

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa244 ◽

2020 ◽

Author(s):

Pablo Garrido-Gil ◽

Ana I Rodriguez-Perez ◽

Lucia Lage ◽

Jose L Labandeira-Garcia

Keyword(s):

Sex Differences ◽

Dopamine Receptors ◽

D2 Receptor ◽

Renin Angiotensin System ◽

Receptor Expression ◽

Oxidative Markers ◽

Mutual Regulation ◽

Inflammatory Processes ◽

Angiotensin Type

Abstract The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been clarified. The dopaminergic system and renin–angiotensin system coexist in the gut and regulate different processes such as motility, absorption/secretion, and inflammation. We investigated the changes in expression of major angiotensin and dopamine receptors in the colon of male, female, and ovariectomized female mice. Possible interaction between both systems was investigated using male and female mice deficient (ko) for major angiotensin and dopamine receptors. In wild-type mice, colonic tissue from females showed lower angiotensin type 1/angiotensin type 2 ratio (an index of pro-inflammatory/anti-inflammatory renin–angiotensin system balance), lower dopamine D1 and D2 receptor expression, and lower levels of pro-inflammatory and pro-oxidative markers relative to males. Interestingly, ovariectomy increased the expression of pro-inflammatory angiotensin type 1 receptor expression and decreased anti-inflammatory angiotensin type 2 receptor expression, increased D1 and D2 receptor expression, and increased the levels of pro-inflammatory and pro-oxidative markers. Ovariectomy-induced changes were blocked by estrogen replacement. The present results suggest a mutual regulation between colonic angiotensin and dopamine receptors and sex differences in this mutual regulation. Estrogen regulates changes in both angiotensin and dopamine receptor expression, which may be involved in sex- and surgical menopause-related effects on gut motility, permeability, and vulnerability to inflammatory processes.

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Intermittent hypoxia prior to completion of nephrogenesis increases systolic blood pressure and proteinuria after angiotensin II treatment in adult male rats

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.593.6 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Lindsey A Ramirez ◽

Elizabeth Snyder ◽

Terri Marin ◽

Jennifer C Sullivan

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Systolic Blood Pressure ◽

Adult Male ◽

Intermittent Hypoxia ◽

Male Rats

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Abstract 309: Sp-3 But not the NF-kB Transcription Factor Causes the Up-regulation of Angiotensin Type 1 Receptor Expression and Contributes to Hypertension in Aging FBN rats.

Hypertension ◽

10.1161/hyp.64.suppl_1.309 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Mohammad Saleem ◽

Mohammad Asghar

Keyword(s):

Blood Pressure ◽

Transcription Factors ◽

At1 Receptor ◽

Receptor Expression ◽

Receptor Protein ◽

Receptor Function ◽

Receptor Mrna ◽

Hk2 Cells ◽

Angiotensin Type

We recently reported that age-associated oxidative stress is causal to higher renal angiotensin Type 1 (AT1) receptor function and hypertension in aged Fisher 344 X Brown Norway (FBN) rats. We became interested in examining the mechanism of higher AT1 receptor function in the aging kidneys. Adult (3-month) and aging (21 month) FBN rats were subjected to conscious blood pressure measurement by telemetry approach. The levels of AT1 receptor mRNA in the kidney cortex was measured by qRT-PCR while nuclear Sp-3 and NF-kB-p65 redox-sensitive transcription factors were determined by western blotting. We found that blood pressure was higher in aged than in adult rats (adult vs. old: 110±1 vs. 130±1 mmHg) which was associated with higher AT1 receptor mRNA levels (adult vs. old: 1.51±0.72 vs. 7.86±1.03 DU), and nuclear levels of both Sp-3 (adult vs. old: 0.56±.01 vs. 1.54±.02 DU) and NF-kB-p65 (adult vs. old: 0.9±.01 vs. 1.5±0.01 DU). To further delineate whether sp-3 or NF-kB-p65 or both transcription factors are responsible for the up-regulation of AT1 receptor, human kidney (HK2) cells were transfected with Sp-3 and NF-kB-p65 plasmids. We found that Sp-3 plasmid but not NF-κB-p65 plasmid transfection caused an increase in the levels of AT1 receptor protein in HK2 cells (control vs. transfected: 135±22 vs. 235±10 DU). Furthermore, Sp-3 siRNA treatment resulted in the reduction of Sp-3 (control vs. transfected: 136±10 vs. 93±21 DU) and AT1 receptor protein levels (control vs. transfected: 270±38 vs. 172±201 DU) in HK2 cells. Our results suggest that sp-3 but not the NF-κB-p65 is involved in the up-regulation of renal AT1 receptor that may be contributing to hypertension in aging FBN rats.

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Changes in angiotensin type 1 receptor binding and angiotensin-induced pressor responses in the rostral ventrolateral medulla of angiotensinogen knockout mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00462.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. R411-R418 ◽

Cited By ~ 4

Author(s):

Daian Chen ◽

Lisa Hazelwood ◽

Lesley L. Walker ◽

Brian J. Oldfield ◽

Michael J. McKinley ◽

...

Keyword(s):

Blood Pressure ◽

Receptor Binding ◽

Knockout Mice ◽

Pressor Response ◽

Ventrolateral Medulla ◽

Ang Ii ◽

Wild Type ◽

Intravenous Injections ◽

Angiotensin Type

ANG II, the main circulating effector hormone of the renin-angiotensin system, is produced by enzymatic cleavage of angiotensinogen. The present study aimed to examine whether targeted deletion of the angiotensinogen gene ( Agt) altered brain ANG II receptor density or responsiveness to ANG II. In vitro autoradiography was used to examine the distribution and density of angiotensin type 1 (AT1) and type 2 receptors. In most brain regions, the distribution and density of angiotensin receptors were similar in brains of Agt knockout mice ( Agt −/− ) and wild-type mice. In Agt −/− mice, a small increase in AT1 receptor binding was observed in the rostral ventrolateral medulla (RVLM), a region that plays a critical role in blood pressure regulation. To examine whether Agt −/− mice showed altered responses to ANG II, blood pressure responses to intravenous injection (0.01–0.1 μg/kg) or RVLM microinjection (50 pmol in 50 nl) of ANG II were recorded in anesthetized Agt −/− and wild-type mice. Intravenous injections of phenylephrine (4 μg/kg and 2 μg/kg) were also made in both groups. The magnitude of the pressor response to intravenous injections of ANG II or phenylephrine was not different between Agt −/− and wild-type mice. Microinjection of ANG II into the RVLM induced a pressor response, which was significantly smaller in Agt −/− compared with wild-type mice (+10 ± 1 vs. +23 ± 4 mmHg, respectively, P = 0.004). Microinjection of glutamate into the RVLM (100 pmol in 10 nl) produced a robust pressor response, which was not different between Agt −/− and wild-type mice. A diminished response to ANG II microinjection in the RVLM of Agt −/− mice, despite an increased density of AT1 receptors suggests that signal transduction pathways may be altered in RVLM neurons of Agt −/− mice, resulting in attenuated cellular excitation.

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Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular–Subventricular Zone

Cells ◽

10.3390/cells8121551 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1551 ◽

Cited By ~ 9

Author(s):

Maria Garcia-Garrote ◽

Ana Perez-Villalba ◽

Pablo Garrido-Gil ◽

German Belenguer ◽

Juan A. Parga ◽

...

Keyword(s):

Adult Neurogenesis ◽

Subventricular Zone ◽

Functional Dependence ◽

Renin Angiotensin System ◽

At1 Receptor ◽

Receptor Expression ◽

At2 Receptor ◽

Angiotensin Type

The renin–angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.

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