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  • 1
    Online Resource
    Online Resource
    Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 296, No. 2 ( 2009-02), p. R309-R317
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 296, No. 2 ( 2009-02), p. R309-R317
    Abstract: Exposure to clinically relevant doses of glucocorticoids during fetal life increases blood pressure in adult male and female sheep. The purpose of this study was to evaluate the effects of prenatal exposure to betamethasone at 80–81 days of gestation on renal function in ewes and rams at 1.5 yr of age. In prenatal betamethasone-exposed males, compared with the vehicle-exposed animals, basal glomerular filtration rate (GFR) (1.93 ± 0.08 vs. 2.27 ± 0.10 ml·min −1 ·kg body wt −1 ) and the ability to excrete an acute Na + load (37.1 ± 4.4 vs. 53.7 ± 9.7%) were reduced. ( P 〈 0.03 and P = 0.03, respectively). In contrast, prenatal betamethasone exposure had no effect on basal GFR, Na + excretion, or the percentage of the Na + load excreted during the experiment in females. Systemic infusions of ANG-(1–7) at 9 ng·min −1 ·kg −1 for 2 h had minimal effects on basal GFR, renal plasma flow, and Na + excretion in males but increased Na + excretion in females. However, the percentage of Na + load excreted during ANG-(1–7) infusion did not change in prenatal betamethasone-exposed females (113.1 ± 14.2 vs. 98.1 ± 12.2%) compared with the significant increase in vehicle females (139.2 ± 22.3 vs. 92.2 ± 7.5%) ( P = 0.01). The data indicate that antenatal betamethasone exposure produces gender-specific alternations in renal function and thus suggest that different mechanisms underlie the antenatal steroid-induced elevations in blood pressure in male and female offspring.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.90645.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    An angiotensin-(1–7) peptidase in the kidney cortex, proximal tubules, and human HK-2 epithelial cells that is distinct from insulin-degrading enzyme
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Renal Physiology Vol. 308, No. 6 ( 2015-03-15), p. F594-F601
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 308, No. 6 ( 2015-03-15), p. F594-F601
    Abstract: Angiotensin 1–7 [ANG-(1–7)] is expressed within the kidney and exhibits renoprotective actions that antagonize the inflammatory, fibrotic, and pro-oxidant effects of ANG II. We previously identified an peptidase that preferentially metabolized ANG-(1–7) to ANG-(1–4) in the brain medulla and cerebrospinal fluid (CSF) of sheep (Marshall AC, Pirro NT, Rose JC, Diz DI, Chappell MC. J Neurochem 130: 313–323, 2014); thus the present study established the expression of the peptidase in the kidney. Utilizing a sensitive HPLC-based approach, we demonstrate a peptidase activity that hydrolyzed ANG-(1–7) to ANG-(1–4) in the sheep cortex, isolated tubules, and human HK-2 renal epithelial cells. The peptidase was markedly sensitive to the metallopeptidase inhibitor JMV-390; human HK-2 cells expressed subnanomolar sensitivity (IC 50 = 0.5 nM) and the highest specific activity (123 ± 5 fmol·min −1 ·mg −1 ) compared with the tubules (96 ± 12 fmol·min −1 ·mg −1 ) and cortex (107 ± 9 fmol·min −1 ·mg −1 ). The peptidase was purified 41-fold from HK-2 cells; the activity was sensitive to JMV-390, the chelator o-phenanthroline, and the mercury-containing compound p-chloromercuribenzoic acid (PCMB), but not to selective inhibitors against neprilysin, neurolysin and thimet oligopeptidase. Both ANG-(1–7) and its endogenous analog [Ala 1 ]-ANG-(1–7) (alamandine) were preferentially hydrolyzed by the peptidase compared with ANG II, [Asp 1 ]-ANG II, ANG I, and ANG-(1–12). Although the ANG-(1–7) peptidase and insulin-degrading enzyme (IDE) share similar inhibitor characteristics of a metallothiolendopeptidase, we demonstrate marked differences in substrate specificity, which suggest these peptidases are distinct. We conclude that an ANG-(1–7) peptidase is expressed within the renal proximal tubule and may play a potential role in the renal renin-angiotensin system to regulate ANG-(1–7) tone.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00609.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477287-5
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  • 3
    Online Resource
    Online Resource
    Enhanced activity of an angiotensin-(1–7) neuropeptidase in glucocorticoid-induced fetal programming
    Elsevier BV ; 2014
    In:  Peptides Vol. 52 ( 2014-02), p. 74-81
    Details
    In: Peptides, Elsevier BV, Vol. 52 ( 2014-02), p. 74-81
    Type of Medium: Online Resource
    ISSN: 0196-9781
    URL: Article
    DOI: 10.1016/j.peptides.2013.12.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2019194-7
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  • 4
    Online Resource
    Online Resource
    Abstract 177: Antenatal Betamethasone Exposure Reduces Ang-(1-7) but Enhances Angiotensin-Converting Enzyme and a Thiol Peptidase to Metabolize Ang-(1-7) in the Cerebrospinal Fluid
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 62, No. suppl_1 ( 2013-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
    Abstract: Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these programming events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. The BM-exposed (BMX) offspring develop elevated blood pressure, decreased baroreflex sensitivity, and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6-months of age. While components of the RAS are present in cerebrospinal fluid (CSF), it is not known if BM exposure influences the CSF RAS to the same extent as other tissue compartments. Therefore, we characterized the CSF RAS in 6-month old male sheep, and established the impact of antenatal exposure on the RAS. Consistent with our previous findings of predominant ACE2 activity in the choroid plexus, CSF Ang-(1-7) levels are significantly higher than Ang I (320.8 ± 96.0 vs. 19.3 ± 4.6 pM; p 〈 0.01, N = 12) or Ang II (1.4 ± 0.5 pM; p 〈 0.01, N = 12). Moreover, Ang-(1-7) was 70% lower in the CSF of the BMX group (97.3 ± 31.4 pM; p 〈 0.05) without changes in Ang I or Ang II. We next assessed the metabolism of Ang-(1-7) in the CSF and demonstrate a trend for increased enzyme activity in BMX males. Further analysis revealed two peptidases that contribute to Ang-(1-7) degradation in CSF of both groups. ACE accounted for approximately 15% (85 out of 100) of the overall Ang-(1-7) metabolism that hydrolyzed the peptide to Ang-(1-5) in CSF and ACE was 1.4-fold higher in the BMX group (6.5 ± 0.5 vs. 8.8 ± 0.5 fmol/min/ml; p 〈 0.02, N = 4). We also identified a novel thiol peptidase activity (Ki = 4 μM PCMB) as the predominant activity that metabolized Ang-(1-7) to Ang-(1-4) in CSF; kinetic analysis of this peptidase in pooled CSF revealed Km and Vmax constants of 5.4 μM and 54 nmol/min/mg for control, and 4 μM and 60 nmol/min/mg for BMX. In summary, CSF levels of Ang-(1-7) were markedly lower following antenatal exposure. The reduced expression of central Ang-(1-7) potentially through an enhanced metabolism pathway may contribute to the long-term increase in blood pressure and an attenuated baroreflex in this model of fetal programming.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.62.suppl_1.A177
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 2094210-2
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  • 5
    Online Resource
    Online Resource
    Fetal betamethasone exposure attenuates angiotensin-(1-7)-Mas receptor expression in the dorsal medulla of adult sheep
    Elsevier BV ; 2013
    In:  Peptides Vol. 44 ( 2013-06), p. 25-31
    Details
    In: Peptides, Elsevier BV, Vol. 44 ( 2013-06), p. 25-31
    Type of Medium: Online Resource
    ISSN: 0196-9781
    URL: Article
    DOI: 10.1016/j.peptides.2013.03.018
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 2019194-7
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  • 6
    Online Resource
    Online Resource
    Plasma and Renal Renin Concentrations in Adult Sheep After Prenatal Betamethasone Exposure
    Springer Science and Business Media LLC ; 2008
    In:  Reproductive Sciences Vol. 15, No. 8 ( 2008-10), p. 831-838
    Details
    In: Reproductive Sciences, Springer Science and Business Media LLC, Vol. 15, No. 8 ( 2008-10), p. 831-838
    Type of Medium: Online Resource
    ISSN: 1933-7191 , 1933-7205
    URL: Article
    DOI: 10.1177/1933719108318599
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2266096-3
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  • 7
    Online Resource
    Online Resource
    Antenatal betamethasone exposure alters renal responses to angiotensin-(1–7) in uninephrectomized adult male sheep
    Hindawi Limited ; 2013
    In:  Journal of the Renin-Angiotensin-Aldosterone System Vol. 14, No. 4 ( 2013-12), p. 290-298
    Details
    In: Journal of the Renin-Angiotensin-Aldosterone System, Hindawi Limited, Vol. 14, No. 4 ( 2013-12), p. 290-298
    Type of Medium: Online Resource
    ISSN: 1470-3203 , 1752-8976
    URL: Article
    DOI: 10.1177/1470320312465217
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2013
    detail.hit.zdb_id: 2261873-9
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  • 8
    Online Resource
    Online Resource
    Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 305, No. 7 ( 2013-10-01), p. R679-R688
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 305, No. 7 ( 2013-10-01), p. R679-R688
    Abstract: Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1–7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P 〈 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min −1 ·ml −1 ; P 〈 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1–7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1–7) levels in exposed animals.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00321.2013
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Evidence for an angiotensin‐(1‐7) neuropeptidase expressed in the brain medulla and CSF of sheep
    Wiley ; 2014
    In:  Journal of Neurochemistry Vol. 130, No. 2 ( 2014-07), p. 313-323
    Details
    In: Journal of Neurochemistry, Wiley, Vol. 130, No. 2 ( 2014-07), p. 313-323
    Abstract: Angiotensin‐(1‐7) [Ang‐(1‐7)] is an alternative product of the brain renin‐angiotensin system that exhibits central actions to lower blood pressure and improve baroreflex sensitivity. We previously identified a peptidase that metabolizes Ang‐(1‐7) to the inactive metabolite product Ang‐(1‐4) in CSF of adult sheep. This study purified the peptidase 1445‐fold from sheep brain medulla and characterized this activity. The peptidase was sensitive to the chelating agents o‐phenanthroline and EDTA, as well as the mercury compound p‐chloromercuribenzoic acid (PCMB). Selective inhibitors to angiotensin‐converting enzyme, neprilysin, neurolysin, and thimet oligopeptidase did not attenuate activity; however, the metallopeptidase agent JMV‐390 was a potent inhibitor of Ang‐(1‐7) hydrolysis (Ki = 0.8 nM). Kinetic studies using 125 I‐labeled Ang‐(1‐7), Ang II, and Ang I revealed comparable apparent K m values (2.6, 2.8, and 4.3 μM, respectively), but a higher apparent V max for Ang‐(1‐7) (72 vs. 30 and 6 nmol/min/mg, respectively; p   〈  0.01). HPLC analysis of the activity confirmed the processing of unlabeled Ang‐(1‐7) to Ang‐(1‐4) by the peptidase, but revealed 〈  5% hydrolysis of Ang II or Ang I, and no hydrolysis of neurotensin, bradykinin or apelin‐13. The unique characteristics of the purified neuropeptidase may portend a novel pathway to influence actions of Ang‐(1‐7) within the brain. image Angiotensin‐(1‐7) actions are mediated by the AT 7 /Mas receptor and include reduced blood pressure, decreased oxidative stress, enhanced baroreflex sensitivity, and increased nitric oxide (NO). Ang‐(1‐7) is directly formed from Ang I by neprilysin (NEP). We identify a new pathway for Ang‐(1‐7) metabolism in the brain distinct from angiotensin‐converting enzyme‐dependent hydrolysis. The Ang‐(1‐7) endopeptidase (A7‐EP) degrades the peptide to Ang‐(1‐4) and may influence central Ang‐(1‐7) tone.
    Type of Medium: Online Resource
    ISSN: 0022-3042 , 1471-4159
    URL: Issue
    URL: Article
    DOI: 10.1111/jnc.2014.130.issue-2
    DOI: 10.1111/jnc.12720
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2020528-4
    SSG: 12
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  • 10
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    Online Resource
    Central Angiotensin-(1–7) Improves Vagal Function Independent of Blood Pressure in Hypertensive (mRen2)27 Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. 5 ( 2012-11), p. 1257-1265
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. 5 ( 2012-11), p. 1257-1265
    Abstract: Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity for heart rate control and high nicotinamide adenine dinucleotide phosphate oxidase and kinase-to-phosphatase signaling activity in medullary tissue compared with normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin II actions, supplementing angiotensin-(1–7), or scavenging reactive oxygen species in brain differentially alters mean arterial pressure, baroreflex sensitivity, or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular infusions of the angiotensin II type 1 receptor antagonist candesartan (4 μg/5 μL/h), angiotensin-(1–7) (0.1 μg/5 μL/h), a reactive oxygen species scavenger tempol (25 μg/5 μL/h), or artificial cerebrospinal fluid (5 μL/h) for 2 weeks. Mean arterial pressure was reduced in candesartan-treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, angiotensin-(1–7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower mean arterial pressure. Tempol significantly reduced nicotinamide adenine dinucleotide phosphate oxidase activity in brain dorsal medullary tissue but had no effect on mean arterial pressure or autonomic function. Candesartan tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase signaling pathways in dorsal medulla. Although additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary nicotinamide adenine dinucleotide phosphate oxidase or mitogen-activated protein kinase in hypertensive (mRen2)27 rats.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.112.196782
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 2094210-2
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