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  • American Physiological Society  (15)
  • 1
    Online Resource
    Online Resource
    Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 314, No. 4 ( 2018-04-01), p. H796-H804
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 314, No. 4 ( 2018-04-01), p. H796-H804
    Abstract: The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na + and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00616.2017
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    The neuronal (pro)renin receptor and astrocyte inflammation in the central regulation of blood pressure and blood glucose in mice fed a high-fat diet
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 318, No. 5 ( 2020-05-01), p. E765-E778
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 318, No. 5 ( 2020-05-01), p. E765-E778
    Abstract: We report here that the neuronal (pro)renin receptor (PRR), a key component of the brain renin-angiotensin system (RAS), plays a critical role in the central regulation of high-fat-diet (HFD)-induced metabolic pathophysiology. The neuronal PRR is known to mediate formation of the majority of angiotensin (ANG) II, a key bioactive peptide of the RAS, in the central nervous system and to regulate blood pressure and cardiovascular function. However, little is known about neuronal PRR function in overnutrition-related metabolic physiology. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity, and fasting blood glucose and improves glucose tolerance without affecting food intake or body weight following a 16-wk HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand (pro)renin in the circulation and hypothalamus and of ANG II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-κB p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00406.2019
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1–7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Renal Physiology Vol. 300, No. 3 ( 2011-03), p. F749-F755
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 300, No. 3 ( 2011-03), p. F749-F755
    Abstract: Alterations in the balance between ANG II/ACE and ANG 1–7/ACE2 in ANG II-dependent hypertension could reduce the generation of ANG 1–7 and contribute further to increased intrarenal ANG II. Upregulation of collecting duct (CD) renin may lead to increased ANG II formation during ANG II-dependent hypertension, thus contributing to this imbalance. We measured ANG I, ANG II, and ANG 1–7 contents, angiotensin-converting enzyme (ACE) and ACE2 gene expression, and renin activity in the renal cortex and medulla in the clipped kidneys (CK) and nonclipped kidneys (NCK) of 2K1C rats. After 3 wk of unilateral renal clipping, systolic blood pressure and plasma renin activity increased in 2K1C rats ( n = 11) compared with sham rats ( n = 9). Renal medullary angiotensin peptide levels were increased in 2K1C rats [ANG I: (CK = 171 ± 4; NCK = 251 ± 8 vs. sham = 55 ± 3 pg/g protein; P 〈 0.05); ANG II: (CK = 558 ± 79; NCK = 328 ± 18 vs. sham = 94 ± 7 pg/g protein; P 〈 0.001)]; and ANG 1–7 levels decreased (CK = 18 ± 2; NCK = 19 ± 2 pg/g vs. sham = 63 ± 10 pg/g; P 〈 0.001). In renal medullas of both kidneys of 2K1C rats, ACE mRNA levels and activity increased but ACE2 decreased. In further studies, we compared renal ACE and ACE2 mRNA levels and their activities from chronic ANG II-infused ( n = 6) and sham-operated rats ( n = 5). Although the ACE mRNA levels did not differ between ANG II rats and sham rats, the ANG II rats exhibited greater ACE activity and reduced ACE2 mRNA levels and activity. Renal medullary renin activity was similar in the CK and NCK of 2K1C rats but higher compared with sham. Thus, the differential regulation of ACE and ACE2 along with the upregulation of CD renin in both the CK and NCK in 2K1C hypertensive rats indicates that they are independent of perfusion pressure and contribute to the altered content of intrarenal ANG II and ANG 1–7.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00383.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477287-5
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  • 4
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    Online Resource
    (Pro)renin receptor regulates lung development via the Wnt/β-catenin signaling pathway
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 317, No. 2 ( 2019-08-01), p. L202-L211
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 317, No. 2 ( 2019-08-01), p. L202-L211
    Abstract: The (pro)renin receptor [(P)RR] binds to prorenin to activate the renin-angiotensin system and is essential for the development of many different organ systems. Whether the (P)RR also plays a role in lung development is unknown. Immunostaining was used to determine the spatial-temporal distribution of (P)RR in the embryonic, postnatal, and adult lungs. We created a lung-specific (P)RR knockout mouse [ Foxd1 cre/+ -(P)RR flox/flox ] and assessed changes in lung morphology, cell proliferation, and apoptosis using immunohistochemistry and TUNEL staining. (P)RR function was confirmed by using siRNA to knock down (P)RR in human bronchial epithelial cells (HBECs) and then using the CCK-8 assay and flow cytometry to assess cell proliferation and apoptosis. Gene expression changes after knockdown were assessed by RT-PCR and Western blotting. (P)RR is expressed in the club cells of the bronchial epithelium, and expression increases throughout development. Lung-specific (P)RR knockout disrupted branching morphogenesis, leading to lung hypoplasia and neonatal mortality. These defects were associated with increased apoptosis and decreased proliferation of the pulmonary epithelial and mesenchymal cells and may be mediated by downregulation of Wnt11, β-catenin, and Axin2. (P)RR regulates lung development through canonical Wnt/β-catenin signaling and may present a new target for strategies to treat lung hypoplasia.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00295.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    The (pro)renin receptor and body fluid homeostasis
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 305, No. 2 ( 2013-07-15), p. R104-R106
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 305, No. 2 ( 2013-07-15), p. R104-R106
    Abstract: The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00209.2013
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477297-8
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  • 6
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    Online Resource
    (Pro)renin receptor knockdown in the paraventricular nucleus of the hypothalamus attenuates hypertension development and AT 1 receptor-mediated calcium events
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 316, No. 6 ( 2019-06-01), p. H1389-H1405
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 316, No. 6 ( 2019-06-01), p. H1389-H1405
    Abstract: Activation of the brain renin-angiotensin system (RAS) is a pivotal step in the pathogenesis of hypertension. The paraventricular nucleus (PVN) of the hypothalamus is a critical part of the angiotensinergic sympatho-excitatory neuronal network involved in neural control of blood pressure and hypertension. However, the importance of the PVN (pro)renin receptor (PVN-PRR)—a key component of the brain RAS—in hypertension development has not been examined. In this study, we investigated the involvement and mechanisms of the PVN-PRR in DOCA-salt-induced hypertension, a mouse model of hypertension. Using nanoinjection of adeno-associated virus-mediated Cre recombinase expression to knock down the PRR specifically in the PVN, we report here that PVN-PRR knockdown attenuated the enhanced blood pressure and sympathetic tone associated with hypertension. Mechanistically, we found that PVN-PRR knockdown was associated with reduced activation of ERK (extracellular signal-regulated kinase)-1/2 in the PVN and rostral ventrolateral medulla during hypertension. In addition, using the genetically encoded Ca 2+ biosensor GCaMP6 to monitor Ca 2+ -signaling events in the neurons of PVN brain slices, we identified a reduction in angiotensin II type 1 receptor-mediated Ca 2+ activity as part of the mechanism by which PVN-PRR knockdown attenuates hypertension. Our study demonstrates an essential role of the PRR in PVN neurons in hypertension through regulation of ERK1/2 activation and angiotensin II type 1 receptor-mediated Ca 2+ activity. NEW & NOTEWORTHY PRR knockdown in PVN neurons attenuates the development of DOCA-salt hypertension and autonomic dysfunction through a decrease in ERK1/2 activation in the PVN and RVLM during hypertension. In addition, PRR knockdown reduced AT 1a R expression and AT 1 R-mediated calcium activity during hypertension. Furthermore, we characterized the neuronal targeting specificity of AAV serotype 2 in the mouse PVN and validated the advantages of the genetically encoded calcium biosensor GCaMP6 in visualizing neuronal calcium activity in the PVN.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00780.2018
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 7
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    Online Resource
    ANG II-independent prorenin/(pro)renin receptor signaling pathways in the central nervous system
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 309, No. 5 ( 2015-09), p. H731-H733
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 309, No. 5 ( 2015-09), p. H731-H733
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00526.2015
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 8
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    Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 308, No. 5 ( 2015-03-01), p. R370-R378
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 308, No. 5 ( 2015-03-01), p. R370-R378
    Abstract: Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00366.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 9
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    Online Resource
    The hypothalamus as a key regulator of glucose homeostasis: emerging roles of the brain renin-angiotensin system
    American Physiological Society ; 2023
    In:  American Journal of Physiology-Cell Physiology Vol. 325, No. 1 ( 2023-07-01), p. C141-C154
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 325, No. 1 ( 2023-07-01), p. C141-C154
    Abstract: The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00533.2022
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 10
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    Angiotensin II regulates brain (pro)renin receptor expression through activation of cAMP response element-binding protein
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 309, No. 2 ( 2015-07-15), p. R138-R147
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 309, No. 2 ( 2015-07-15), p. R138-R147
    Abstract: We reported that brain (pro)renin receptor (PRR) expression levels are elevated in DOCA-salt-induced hypertension; however, the underlying mechanism remained unknown. To address whether ANG II type 1 receptor (AT 1 R) signaling is involved in this regulation, we implanted a DOCA pellet and supplied 0.9% saline as the drinking solution to C57BL/6J mice. Sham pellet-implanted mice that were provided regular drinking water served as controls. Concurrently, mice were intracerebroventricularly infused with the AT 1 R blocker losartan, angiotensin-converting-enzyme inhibitor captopril, or artificial cerebrospinal fluid for 3 wk. Intracerebroventricular infusion of losartan or captopril attenuated DOCA-salt-induced PRR mRNA elevation in the paraventricular nucleus of the hypothalamus, suggesting a role for ANG II/AT 1 R signaling in regulating PRR expression during DOCA-salt hypertension. To test which ANG II/AT 1 R downstream transcription factors were involved in PRR regulation, we treated Neuro-2A cells with ANG II with or without CREB (cAMP response element-binding protein) or AP-1 (activator protein-1) inhibitors, or CREB siRNA. CREB and AP-1 inhibitors, as well as CREB knockdown abolished ANG II-induced increases in PRR levels. ANG II also induced PRR upregulation in primary cultured neurons. Chromatin immunoprecipitation assays revealed that ANG II treatment increased CREB binding to the endogenous PRR promoter in both cultured neurons and hypothalamic tissues of DOCA-salt hypertensive mice. This increase in CREB activity was reversed by AT 1 R blockade. Collectively, these findings indicate that ANG II acts via AT 1 R to upregulate PRR expression both in cultured cells and in DOCA-salt hypertensive mice by increasing CREB binding to the PRR promoter.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00319.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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