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Lu W, Wang Y, Fang Z, Wang H, Zhu J, Zhai Q, Zhao J, Zhang H, Chen W. Bifidobacterium longum CCFM752 prevented hypertension and aortic lesion, improved antioxidative ability, and regulated the gut microbiome in spontaneously hypertensive rats. Food Funct 2022; 13:6373-6386. [PMID: 35615892 DOI: 10.1039/d1fo04446j] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Oxidative stress and gut dysbiosis are important risk factors for hypertension. In this study, the preventive effect of Bifidobacterium longum CCFM752 (CCFM752) on hypertension was evaluated. 5-week-old spontaneously hypertensive rats (SHR) were treated with vehicle or CCFM752 (1.0 × 109 CFU day-1) for 12 weeks. The increase in systolic blood pressure and diastolic blood pressure was significantly prevented by CCFM752 treatment. Simultaneously, CCFM752 prevented aortic fibrosis and hypertrophy and increased aortic endothelial nitric oxide synthase (eNOS) activity. CCFM752 presented an antioxidative effect by inhibiting aortic NADPH oxidase activation and increasing aortic and serum catalase activity, and reducing aortic reactive oxygen species (ROS). The gut dysbiosis of SHR, including the increased Firmicutes/Bacteroidetes ratio, decreased Actinobacteria as well as reduced α-diversity, were restored by CCFM752. CCFM752 also increased the prevalence of Bifidobacterium and Lactobacillus, while decreasing Turicibacter at the genus level. Furthermore, serum metabolomic analysis revealed that CCFM752 up-regulated serum proline and pyridoxamine 5'-phosphate, both of which were negatively correlated with blood pressure. In conclusion, the positive impact of CCFM752 on the gut microbiota may contribute to the antioxidative effect as well as its preventive effect on hypertension.
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Affiliation(s)
- Wenwei Lu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China.,National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, 214122, PR China
| | - Yusheng Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Zhifeng Fang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Hongchao Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Jinlin Zhu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China.,National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, 214122, PR China.,Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi 214122, PR China.,(Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou 225004, PR China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China. .,School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China.,National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, 214122, PR China
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Sinapic Acid Attenuates Cardiovascular Disorders in Rats by Modulating Reactive Oxygen Species and Angiotensin Receptor Expression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1436858. [PMID: 32765804 PMCID: PMC7374234 DOI: 10.1155/2020/1436858] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/20/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022]
Abstract
The main avoidable risk factor for cardiovascular conditions is high blood pressure (hypertension). At global level, hypertension is believed to be responsible for a 54% stroke-related mortality rate and a 47% mortality rate associated with coronary heart disease. It is postulated that sinapic acid (SA) could help in hypertension management because it displays robust antioxidant, antihyperglycemic, and peroxynitrite scavenging effects. To explore this hypothesis, this work examined the effect of SA on oxidative stress and cardiovascular disease in rats with hypertension by comparison against captopril. For this purpose, 50 male rats were used and equally allocated to five groups, namely, normal control, positive control (L-NAME), L-NAME with concomitant captopril administration, L-NAME with concomitant SA administration, and L-NAME with concomitant administration of both SA and captopril. Results showed that, by contrast to control, L-NAME exhibited marked elevation in serum CK-MB, total cholesterol, triglycerides, VLDL-C, LDL-C, Ang II, AT2R, ET-1, and angiopoietin-2; on the other hand, L-NAME exhibited marked reduction in serum HDL-C, superoxide dismutase (SOD) activity, nitric oxide synthase 3 (NOS3), and glutathione (GSH). Furthermore, joint administration of SA and captopril ameliorated hypertension, enhanced cardiovascular function, hindered hyperlipidemia, and decreased oxidative stress and myocardial hypertrophy displayed by rats with hypertension. Based on such findings, better chemopreventive or therapeutic approaches can be devised to manage hypertension and cardiovascular conditions.
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Walton SL, Mazzuca MQ, Tare M, Parkington HC, Wlodek ME, Moritz KM, Gallo LA. Angiotensin receptor blockade in juvenile male rat offspring: Implications for long-term cardio-renal health. Pharmacol Res 2018; 134:320-331. [PMID: 29870806 DOI: 10.1016/j.phrs.2018.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 05/21/2018] [Accepted: 06/01/2018] [Indexed: 11/25/2022]
Abstract
Inhibition of the renin-angiotensin system in early postnatal life is a potential therapeutic approach to prevent long-term cardiovascular and kidney diseases in individuals born small. We determined the long-term effects of juvenile losartan treatment on cardiovascular and kidney function in control male rat offspring and those exposed to uteroplacental insufficiency and born small. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed in late gestation in Wistar Kyoto rats. At weaning, male offspring were randomly assigned to receive losartan in their drinking water or drinking water alone from 5 to 8 weeks of age, and followed to 26 weeks of age. Systolic blood pressure and kidney function were assessed throughout the study. Pressure myography was used to assess passive mechanical wall properties in mesenteric and femoral arteries from 26-week-old offspring. Losartan treatment for three weeks lowered systolic blood pressure in both Control and Restricted groups but this difference was not sustained after the cessation of treatment. Losartan, irrespective of birth weight, mildly increased renal tubulointerstitial fibrosis when assessed at 26 weeks of age. Mesenteric artery stiffness was increased by the early losartan treatment, and was associated with increased collagen and decreased elastin content. Losartan also exerted long-term increases in fat mass and decreases in skeletal muscle mass. In this study, untreated Restricted offspring did not develop hypertension, vascular dysfunction or kidney changes as anticipated. Regardless, we demonstrate that short-term losartan treatment in the juvenile period negatively affects postnatal growth, and kidney and vascular parameters in adulthood, irrespective of birth weight. The long-term effects of early-life losartan treatment warrant further consideration in settings where the potential benefits may outweigh the risks; i.e. when programmed adulthood diseases are apparent and in childhood cardiovascular and kidney diseases.
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Affiliation(s)
- Sarah L Walton
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia; Child Health Research Centre, The University of Queensland, South Brisbane, QLD, Australia
| | - Marc Q Mazzuca
- Department of Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Marianne Tare
- Department of Physiology, Monash University, Clayton, VIC, Australia; Monash Rural Health, Churchill, VIC, Australia
| | | | - Mary E Wlodek
- Department of Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Karen M Moritz
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia; Child Health Research Centre, The University of Queensland, South Brisbane, QLD, Australia.
| | - Linda A Gallo
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia; Department of Physiology, The University of Melbourne, Parkville, VIC, Australia; Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
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Nakamori H, Yoshida SI, Ishiguro H, Suzuki S, Yasuzaki H, Hashimoto T, Ishigami T, Hirawa N, Toya Y, Umemura S, Tamura K. Arterial wall hypertrophy is ameliorated by α2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice. Clin Exp Nephrol 2017; 22:773-781. [PMID: 29230587 DOI: 10.1007/s10157-017-1520-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 12/04/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg -/-) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-β1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-β1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required. METHODS We performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg -/- mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-β1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis. RESULTS Norepinephrine content in kidneys of Atg -/- mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-β1 gene in kidneys of Atg -/- mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced α2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg -/- mice, which lack renin substrate. CONCLUSIONS Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg -/- mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of α2-ARs. Although renal arterial hypertrophy in Atg -/- mice appears to be of multifactorial origin, TGF-β1 may play a key role in the persistence of such hypertrophy.
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Affiliation(s)
- Haruka Nakamori
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Shin-Ichiro Yoshida
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Hiroaki Ishiguro
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Shota Suzuki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Hiroaki Yasuzaki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Tatsuo Hashimoto
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Tomoaki Ishigami
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Nobuhito Hirawa
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Yoshiyuki Toya
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Satoshi Umemura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
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Nakanishi K, Nagai Y, Akimoto T, Yamanaka N. Changes in renal vessels associated with long-term administration of angiotensin converting enzyme inhibitor in Zucker fatty rats. J Smooth Muscle Res 2017; 53:20-30. [PMID: 28260705 PMCID: PMC5364377 DOI: 10.1540/jsmr.53.20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background Recently, we showed that long-term angiotensin receptor blocker (ARB) administration induced unusual proliferative changes in smooth muscle cells (SMCs) of afferent arterioles of the kidneys of Zucker fatty rats (ZFRs). In this study, we investigated renal afferent arteriolar changes induced by the long-term administration of an angiotensin converting enzyme inhibitor (ACEI) in ZFRs. Materials and Methods Fourteen 6-week-old male ZFRs were divided into two groups (n=14): the ZFR+ACEI group (n=6) was fed a standard diet containing ACEI (Enalapril, 2 mg/kg/day), and the ZFR control group (n=8) for 12 weeks. Blood pressure and proteinuria were examined and morphological studies on kidneys were performed. Results Remarkable proliferative changes in the afferent arteriolar SMCs were frequently observed in the group given ACEI; (66.1 ± 12.9%) compared with the control group (1.77 ± 1.56%, P<0.001). Conclusions It was indicated that long-term ACEI administration induced unusual proliferative changes in SMCs in afferent arterioles of ZFRs. These changes could reduce intraglomerular pressure by narrowing the lumens of afferent arterioles, but they could cause irreversible damage to the arterioles.
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Affiliation(s)
- Kazushige Nakanishi
- Department of General Medicine and Emergency Care, Faculty of Medicine, Toho University
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Care AS, Sung MM, Panahi S, Gragasin FS, Dyck JRB, Davidge ST, Bourque SL. Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult Offspring. Hypertension 2016; 67:1038-44. [PMID: 26928803 DOI: 10.1161/hypertensionaha.115.06793] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 01/05/2016] [Indexed: 11/16/2022]
Abstract
This study was undertaken to determine whether perinatal maternal resveratrol (Resv)--a phytoalexin known to confer cardiovascular protection--could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with L-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide-independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (-28%; P<0.05), and this difference could be normalized by L-NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats.
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Affiliation(s)
- Alison S Care
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.)
| | - Miranda M Sung
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.)
| | - Sareh Panahi
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.)
| | - Ferrante S Gragasin
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.)
| | - Jason R B Dyck
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.)
| | - Sandra T Davidge
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.)
| | - Stephane L Bourque
- From the Department of Obstetrics and Gynecology (A.S.C., S.T.D.), Department of Pediatrics (M.M.S., J.R.B.D.), Department of Anesthesiology and Pain Medicine (S.P., F.S.G., S.L.B.), Department of Pharmacology (J.R.B.D., S.L.B.), Cardiovascular Research Centre (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), Women and Children's Health Research Institute (A.S.C., M.M.S., F.S.G., J.R.B.D., S.T.D., S.L.B.), University of Alberta, Edmonton, Alberta, Canada; and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (A.S.C.).
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Reprogramming: A Preventive Strategy in Hypertension Focusing on the Kidney. Int J Mol Sci 2015; 17:ijms17010023. [PMID: 26712746 PMCID: PMC4730270 DOI: 10.3390/ijms17010023] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 12/16/2015] [Accepted: 12/17/2015] [Indexed: 01/10/2023] Open
Abstract
Adulthood hypertension can be programmed in response to a suboptimal environment in early life. However, developmental plasticity also implies that one can prevent hypertension in adult life by administrating appropriate compounds during early development. We have termed this reprogramming. While the risk of hypertension has been assessed in many mother-child cohorts of human developmental programming, interventions necessary to prove causation and provide a reprogramming strategy are lacking. Since the developing kidney is particularly vulnerable to environmental insults and blood pressure is determined by kidney function, renal programming is considered key in developmental programming of hypertension. Common pathways, whereby both genetic and acquired developmental programming converge into the same phenotype, have been recognized. For instance, the same reprogramming interventions aimed at shifting nitric oxide (NO)-reactive oxygen species (ROS) balance, such as perinatal citrulline or melatonin supplements, can be protective in both genetic and developmentally programmed hypertension. Furthermore, a significantly increased expression of gene Ephx2 (soluble epoxide hydrolase) was noted in both genetic and acquired animal models of hypertension. Since a suboptimal environment is often multifactorial, such common reprogramming pathways are a practical finding for translation to the clinic. This review provides an overview of potential clinical applications of reprogramming strategies to prevent programmed hypertension. We emphasize the kidney in the following areas: mechanistic insights from human studies and animal models to interpret programmed hypertension; identified risk factors of human programmed hypertension from mother-child cohorts; and the impact of reprogramming strategies on programmed hypertension from animal models. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies.
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Igreja B, Wright LC, Soares-da-Silva P. Sustained high blood pressure reduction with etamicastat, a peripheral selective dopamine β-hydroxylase inhibitor. ACTA ACUST UNITED AC 2015; 10:207-16. [PMID: 26803288 DOI: 10.1016/j.jash.2015.12.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 12/03/2015] [Accepted: 12/16/2015] [Indexed: 11/25/2022]
Abstract
The aim of the present study was to evaluate the influence of chronic inhibition of dopamine ß-hydroxylase by etamicastat on the development of hypertension in the spontaneously hypertensive rat (SHR) and the sustainability of effects on the systolic and diastolic blood pressure in the SHR and the normotensive Wistar-Kyoto rat (WKY). WKY and SHR received etamicastat (10 mg/kg/d) from 5 weeks of age for 35 weeks in drinking water, and cardiovascular assessments were performed on a weekly basis. Etamicastat reduced systolic and diastolic blood pressure when SHRs reached the age of 16 weeks with mean decreases of 37 and 32 mm Hg, respectively, for the subsequent for 24 weeks of treatment, but did not prevent the increase in blood pressure (BP) aged between 5 and 11 week. The BP lowering effect of etamicastat in SHR was reversible on discontinuation and quickly resumed after reinstatement of therapy and was not accompanied by changes in heart rate. Etamicastat affected neither BP nor heart rate in WKY during 36 weeks of treatment. Etamicastat reduced urinary excretion of norepinephrine to a similar extent in WKY and SHR, accompanied by significant increases in urinary dopamine in SHR. Chronic administration of etamicastat did not adversely affected development of animals. Chronic dopamine ß-hydroxylase inhibition with etamicastat effectively decreases BP, although does not prevent the development of hypertension in the SHR.
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Affiliation(s)
- Bruno Igreja
- Department of Research and Development, BIAL-Portela & C(a), S.A., Portugal
| | - Lyndon C Wright
- Department of Research and Development, BIAL-Portela & C(a), S.A., Portugal
| | - Patricio Soares-da-Silva
- Department of Research and Development, BIAL-Portela & C(a), S.A., Portugal; Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Portugal; MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
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Klimas J, Olvedy M, Ochodnicka-Mackovicova K, Kruzliak P, Cacanyiova S, Kristek F, Krenek P, Ochodnicky P. Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats. J Cell Mol Med 2015; 19:1965-74. [PMID: 25766467 PMCID: PMC4549047 DOI: 10.1111/jcmm.12573] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/04/2015] [Indexed: 01/08/2023] Open
Abstract
Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.
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Affiliation(s)
- Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia
| | - Michael Olvedy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia
| | | | - Peter Kruzliak
- Department of Cardiovascular Diseases, International Clinical Research Centre, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic
| | - Sona Cacanyiova
- Institute of Normal and Pathological Physiology, Centre of Excellence for Cardiovascular Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Frantisek Kristek
- Institute of Normal and Pathological Physiology, Centre of Excellence for Cardiovascular Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Peter Krenek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia
| | - Peter Ochodnicky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia
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10
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Albarwani S, Al-Siyabi S, Tanira MO. Prehypertension: Underlying pathology and therapeutic options. World J Cardiol 2014; 6:728-43. [PMID: 25228952 PMCID: PMC4163702 DOI: 10.4330/wjc.v6.i8.728] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 06/08/2014] [Accepted: 06/14/2014] [Indexed: 02/06/2023] Open
Abstract
Prehypertension (PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease (CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably from country to country ranging between 21.9% and 52%. Many hypotheses are proposed to explain the underlying pathophysiology of PHTN. The most notable of these implicate the renin-angiotensin system (RAS) and vascular endothelium. However, other processes that involve reactive oxygen species, the inflammatory cytokines, prostglandins and C-reactive protein as well as the autonomic and central nervous systems are also suggested. Drugs affecting RAS have been shown to produce beneficial effects in prehypertensives though such was not unequivocal. On the other hand, drugs such as β-adrenoceptor blocking agents were not shown to be useful. Leading clinical guidelines suggest using dietary and lifestyle modifications as a first line interventional strategy to curb the progress of PHTN; however, other clinically respected views call for using drugs. This review provides an overview of the potential pathophysiological processes associated with PHTN, abridges current intervention strategies and suggests investigating the value of using the "Polypill" in prehypertensive subjects to ascertain its potential in delaying (or preventing) CVD associated with raised blood pressure in the presence of other risk factors.
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Affiliation(s)
- Sulayma Albarwani
- Sulayma Albarwani, Sultan Al-Siyabi, Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - Sultan Al-Siyabi
- Sulayma Albarwani, Sultan Al-Siyabi, Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - Musbah O Tanira
- Sulayma Albarwani, Sultan Al-Siyabi, Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
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11
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Nagai Y, Nakanishi K, Akimoto T, Yamanaka N. Proliferative changes of renal arteriolar walls induced by administration of angiotensin II receptor blocker are frequent in juvenile rats. J Renin Angiotensin Aldosterone Syst 2013; 15:440-9. [PMID: 24222655 DOI: 10.1177/1470320313502105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Our previous study of angiotensin II receptor blocker (ARB) administration in rats induced unusual proliferative changes of smooth muscle cells in renal arteriolar walls. The present study examined if the incidence of the changes depended on the rats' age, and how long it would take to find changes. MATERIALS AND METHODS Six-week-old (juvenile spontaneous hypertensive rats (SHRs)+ARB group, n=15) and 20-week-old (adult SHRs+ARB group, n=10) male SHRs were fed a standard diet (0.4% NaCl) containing valsartan (10 mg/kg/day; Novartis Co.). Fifteen age-matched SHRs were studied as controls. After 4, 8, and 12 weeks, the rat kidneys were examined under light and electron microscopes and through immunohistochemical studies. RESULTS Extremely concentric proliferative changes in afferent arteriolar walls were frequently observed in the juvenile SHR+ARB group compared to the adult SHR+ARB group (48.7±6.8% vs 19.3±6.9%; p=0.0307) at the 12(th) week. Increased renin expression and arteriolar changes were found from the 4(th) week in the juvenile SHR+ARB group. CONCLUSION This study indicates that ARB administration induces unusual proliferative changes and a marked renin-producing cell increase in afferent arterioles more frequently in juveniles than adult rats. It is suggested that the treatment of ARB in juveniles might have a higher risk of changes in renal afferent arterioles.
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Affiliation(s)
- Yohko Nagai
- Tokyo Kidney Research Institute, Tokyo, Japan Department of General Medicine and Emergency Care, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kazushige Nakanishi
- Department of General Medicine and Emergency Care, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Tatsuo Akimoto
- Department of General Medicine and Emergency Care, Faculty of Medicine, Toho University, Tokyo, Japan
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12
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Renal inflammatory markers during the onset of hypertension in spontaneously hypertensive rats. Hypertens Res 2013; 37:100-9. [PMID: 23985702 DOI: 10.1038/hr.2013.99] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 06/16/2013] [Accepted: 07/01/2013] [Indexed: 12/14/2022]
Abstract
Early blockade of the renin-angiotensin system is successful in delaying the development of hypertension in spontaneously hypertensive rats (SHRs) and ameliorating organ damage by inhibition of the inflammatory response. In this study, we investigated the role of the angiotensin II type 1 receptor (AT1R) in the early renal inflammatory response in SHR. Blood pressure development and renal inflammatory markers were measured in 4-, 8- and 12-week-old SHR and age-matched Wistar Kyoto (WKY) rats. Separate groups of SHRs were transiently treated with the AT1R blocker losartan between 4 and 8 weeks of age. Urinary excretion of the renal injury markers osteopontin and neutrophil gelatinase-associated lipocalin increased in young SHR. Further, renal expression of inflammatory genes was also increased in young SHR. Losartan inhibited the increase of these inflammatory markers. In contrast, gene expression of the renal injury marker and T-cell inducer kidney injury molecule-1 (KIM-1) was reduced in 4-week-old SHR when compared with WKY. Similarly, the T-cell marker CD3 was significantly decreased in 4-week-old SHR. These effects were not antagonized by AT1R blockade. This study confirms the presence of an early renal inflammatory response in SHR that can be blocked by AT1R antagonism. In addition, it demonstrates that KIM-1 does not behave as a pure kidney injury marker in young SHR, but may reflect kidney maturation.
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13
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Abstract
Besides the impact of direct environmental factors, the occurrence of non-communicable adult disease is determined by non-genetic and genetic developmental factors. The broad developmental categories, developmental programing and genetic variation are often viewed as being independent of each other. The object of this review, focusing on hypertension and hypercholesterolemia, is to identify interaction between genetic and non-genetic developmental factors influencing risk factors that can contribute to the occurrence of non-communicable adult disease.
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Affiliation(s)
- Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
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14
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Perinatal inhibition of NF-kappaB has long-term antihypertensive effects in spontaneously hypertensive rats. J Hypertens 2011; 29:1160-6. [DOI: 10.1097/hjh.0b013e3283468344] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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15
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Lee JY, Azar SH. Wistar-Kyoto and spontaneously hypertensive rat blood pressure after embryo transfer into different wombs and cross-suckling. Exp Biol Med (Maywood) 2010; 235:1375-84. [PMID: 20864459 DOI: 10.1258/ebm.2010.010081] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Blood pressure (BP) varies based on genetic and environmental factors. To test genetic and environmental influences on body weight (BW) and BP, one-cell homozygous embryos were transferred into spontaneously hypertensive (SHR, pup:shr) or (Wistar-Kyoto normotensive [WKY], pup:wky) normotensive rats' oviducts (embryos: s,w; oviduct-uterine: S,W), cross-suckled at birth (nurses S,W) and weaned to normal diets at day-21. BP at day-120 was measured by radiotelemetry and analyzed by methods of linear least square rhythmometry and analysis of variance. Genetics dominantly affected shr BP, causing it to be significantly higher at birth (24.6 ± 1.8 in sS versus 21.8 ± 1.7 mmHg in wW, P < 0.005), and at day-120 (198 ± 0.5 in sSS versus 127 ± 0.2 mmHg in wWW, P < 0.001), with lower BW than those of wky (5.3 ± 0.2 versus 5.7 ± 0.2 g at birth, 332 ± 5 versus 404 ± 6 g at day-120, both P < 0.001). Surprisingly, uterine-suckling milieus lowered shr BP significantly at day-120 (198 ± 0.5 in sSS versus 178 ± 0.5, 147 ± 0.6, 179 ± 0.5 mmHg in sSW, sWS, sWW, respectively, all P < 0.01). BP was slightly elevated when wky-genetics were implanted into the S-uterine by 4 mmHg (wSW, P < 0.05), whereas implanting shr embryos into the W-uterine environment (sWS) lowered BP by 51 mmHg (P < 0.001). In summary, the hypertensive shr-strain showed significantly lower BP when provided with an WKY-uterine environment and/or by WKY-nursing mothers, indicating that environment can modify genetic influences; yet the shr MESORs (rhythm-adjusted 24-h mean: midline estimating statistic of rhythm) lowered by WKY environments remained above MESORs encountered in wky-donors.
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Affiliation(s)
- Jong Y Lee
- Department of Medicine, University of Minnesota School of Medicine, P.O. Box 14945, Minneapolis, MN 55414, USA.
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16
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Role of postnatal dietary sodium in prenatally programmed hypertension. Pediatr Nephrol 2009; 24:1727-33. [PMID: 19421785 DOI: 10.1007/s00467-009-1196-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2009] [Revised: 03/12/2009] [Accepted: 03/31/2009] [Indexed: 12/24/2022]
Abstract
In this study we examined the short- and long-term impact of early life dietary sodium (Na) on prenatally programmed hypertension. Hypertension was induced in rat offspring by a maternal low protein (LP) diet. Control and LP offspring were randomized to a high (HS), standard (SS), or low (LS) Na diet after weaning. On the SS diet, the LP pups developed hypertension by 6 weeks of age. The development of hypertension was prevented by the LS diet and exacerbated by the HS diet. Kidney nitrotyrosine content, a measure of oxidative stress, was reduced by the LS diet compared with the HS diet. The modified diets had no effect on control pups. A group of animals on the SS diet was followed up to 51 weeks of age after an early life 3-week exposure to the HS or LS diet. This brief early exposure of LP animals to the LS diet prevented the later development of hypertension and ameliorated the nephrosclerosis observed after early exposure to the HS diet. The LP offspring with early exposure to LS diet had lost their salt-sensitivity when challenged with the HS diet at the age of 43-49 weeks. No effect of early life dietary Na was observed in control animals. These results show that hypertension in this model is salt sensitive and may, in part, be mediated by salt-induced renal oxidative stress and that there may exist a developmental window which allows postnatal "reprogramming" of the hypertension.
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17
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Affiliation(s)
- Harry A.J. Struijker-Boudier
- From the Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, The Netherlands
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18
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Koeners MP, Racasan S, Koomans HA, Joles JA, Braam B. Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L-arginine and antioxidants. Acta Physiol (Oxf) 2007; 190:329-38. [PMID: 17394565 DOI: 10.1111/j.1748-1761.2007.01702.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
AIM Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. METHODS Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. Nomega-nitro-l-arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). RESULTS Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 +/- 4 vs. 33 +/- 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 +/- 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. CONCLUSION Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.
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Affiliation(s)
- M P Koeners
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
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19
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Joles JA, Braam B, Verhaar MC. ACE inhibition and glomerular repair: restructuring or regeneration? Kidney Int 2006; 69:1105-7. [PMID: 16609678 DOI: 10.1038/sj.ki.5000237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In this issue of Kidney International, Andrea Remuzzi et al. convincingly demonstrate glomerular repair in spontaneous renal disease by ACE inhibition. These findings provoke questions about how ACE inhibition (or AT1R blockade) can on the one hand actually repair some diseased kidneys while on the other interfering with normal renal development or the recovery of other diseased kidneys.
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Affiliation(s)
- J A Joles
- Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands.
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20
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McMullen S, Langley-Evans SC. Sex-specific effects of prenatal low-protein and carbenoxolone exposure on renal angiotensin receptor expression in rats. Hypertension 2005; 46:1374-80. [PMID: 16230509 PMCID: PMC1885370 DOI: 10.1161/01.hyp.0000188702.96256.46] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2005] [Accepted: 09/22/2005] [Indexed: 11/16/2022]
Abstract
Experimental models have shown the developing cardiovascular and renal systems to be sensitive to mild shifts in maternal nutrition, leading to altered function and risk of disease in adult life. The offspring of Wistar rats fed a low-protein diet during pregnancy exhibit a reduced nephron number and hypertension in postnatal life, providing a useful tool to examine the mechanistic basis of programming. Evidence indicates that upregulation of the renin-angiotensin system plays an important role, in particular through receptor-mediated changes in angiotensin II activity. However, although programmed hypertension has proven dependent on maternal glucocorticoids, there appear to be conflicting effects of prenatal low-protein and glucocorticoid exposure on postnatal angiotensin receptor expression. This study aimed to resolve this issue by comparing the effects of low-protein and glucocorticoid exposures on postnatal nephron number and angiotensin receptor expression. In addition, this study examined the modulation of prenatal treatment effects by postnatal inhibition of type 1 angiotensin receptor. The data demonstrates that whereas prenatal low-protein and glucocorticoid exposure have a similar effect in reducing nephron number, there are age- and gender-related differences in their effects on postnatal angiotensin receptor expression. In addition, this study provides novel evidence of a substantial upregulation of type 2 angiotensin receptor expression in low-protein- and glucocorticoid-exposed female offspring at 20 weeks of age, with implications for subsequent renal remodeling and function. Despite being targeted to the postnephrogenic period, inhibition of type 1 angiotensin receptor had an inhibitory effect on renal and somatic growth, additionally indicating its unsuitability during early life.
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Affiliation(s)
- Sarah McMullen
- Division of Nutritional Sciences, University of Nottingham, Loughborough, LE12 5RD, United Kingdom
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21
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Wang X, Sun Z, Cade R. Prolonged attenuation of cold-induced hypertension by adenoviral delivery of renin antisense. Kidney Int 2005; 68:680-7. [PMID: 16014045 DOI: 10.1111/j.1523-1755.2005.00446.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Renin has been linked to the pathogenesis of some forms of hypertension, including cold-induced hypertension (CIH). Although several antihypertensive drugs that inhibit angiotensin-converting enzyme (ACE) and angiotensin II (Ang II) type 1 (AT(1)) receptors are available, they are short-lasting and have side effects. Inhibition of renin [the first and rate-limiting step of the renin-angiotensin system (RAS)] would provide an inhibition of the entire RAS. Thus, we developed an antisense approach for specific inhibition of renin based on the genetic design. The objective of this study was to test our hypothesis that adenoviral delivery of renin antisense inhibits renin and attenuates CIH. METHODS Recombinant adenoviruses carrying rat renin antisense (rAdv.RRA) and LacZ reporter gene (rAdv.LacZ) were constructed and used for in vivo gene transfer via intravenous injection. Four groups of rats were used (six rats/group). Blood pressure did not differ among the four groups during the control period at room temperature (25 degrees C). Two groups of rats received rAdv.RRA (2.5 x 10(9) pfu/rat, intravenously), while the other two groups received the same dose of rAdv.LacZ and served as controls. After gene delivery, one rAdv.LacZ-treated and one rAdv.RRA-treated group were exposed to cold (5 degrees C), while the remaining groups were kept at 25 degrees C. Blood pressure was monitored weekly during cold exposure. A 24-hour urine sample was collected during weeks 1, 3, and 5 for measuring urinary aldosterone excretion. At the end of week 5, all animals were killed and blood was collected for measurement of plasma renin activity (PRA), total plasma renin, plasma active renin, and plasma aldosterone. Vascular Ang II contents were measured in all rats. RESULTS Blood pressure of the rAdv.LacZ-treated group rose significantly within 2 weeks of exposure to cold and reached 158.2 +/- 6.4 mm Hg by week 5. In contrast, blood pressure (117.1 +/- 5.3 mm Hg) of the cold-exposed group treated with rAdv.RRA did not increase until 5 weeks after exposure to cold. Thus, a single dose of rAdv.RRA prevented CIH for at least 5 weeks. rAdv.RRA abolished the cold-induced increases in PRA, total plasma renin, plasma active renin, vascular Ang II, and plasma and urine aldosterone, indicating effective inhibition of the entire RAS. CONCLUSION rAdv.RRA effectively inhibited the entire RAS and produced prolonged attenuation of CIH. Antisense inhibition of renin may be a novel and ideal approach for long-term control of hypertension.
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Affiliation(s)
- Xiuqing Wang
- Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA
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22
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Takazawa Y, Maeshima Y, Kitayama H, Yamamoto Y, Kawachi H, Shimizu F, Matsui H, Sugiyama H, Yamasaki Y, Makino H. Infusion of angiotensin II reduces loss of glomerular capillary area in the early phase of anti-Thy-1.1 nephritis possibly via regulating angiogenesis-associated factors. Kidney Int 2005; 68:704-22. [PMID: 16014048 DOI: 10.1111/j.1523-1755.2005.00449.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Hyperphosphatemia in patients with chronic kidney disease leads to secondary hyperparathyroidism and renal osteodystrophy, and it is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphorus below 5.5 mg/dL, calcium-phosphorus (Ca x P) product less than 55 mg(2)/dL(2), intact parathyroid hormone (iPTH) 150 pg/mL to 300 pg/mL, and bicarbonate (HCO(3)) greater than 22 mEq/L. Although calcium-based phosphate binders (CBPB) are cost effective, there are long-term safety concerns pertaining to their postulated role in the progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE) study indicate that calcium acetate is more effective than sevelamer hydrochloride in controlling serum phosphorous, Ca x P product, and HCO(3) in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer hydrochloride had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer hydrochloride is unknown but may relate to decreased calcium loading, or to dramatic reductions in low-density lipoprotein (LDL) cholesterol in sevelamer hydrochloride-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in end-stage renal disease (ESRD) remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer hydrochloride, it remains an accepted first-line phosphate binder. This review examines these issues and provides rational guidelines for the use of CBPB in patients on maintenance hemodialysis.
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MESH Headings
- Angiotensin I/metabolism
- Angiotensin II/metabolism
- Angiotensin II/pharmacology
- Animals
- Blood Pressure
- Capillaries/pathology
- Capillaries/physiology
- Glomerulonephritis/drug therapy
- Glomerulonephritis/pathology
- Glomerulonephritis/physiopathology
- Hypertension, Renal/drug therapy
- Hypertension, Renal/pathology
- Hypertension, Renal/physiopathology
- Immunohistochemistry
- Isoantibodies/pharmacology
- Kidney Glomerulus/blood supply
- Kidney Glomerulus/metabolism
- Kidney Glomerulus/pathology
- Macrophages/pathology
- Male
- Monocytes/pathology
- Neovascularization, Physiologic/drug effects
- Neovascularization, Physiologic/physiology
- Rats
- Rats, Wistar
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 2/metabolism
- Receptor, TIE-2/metabolism
- Time Factors
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Endothelial Growth Factor Receptor-1/metabolism
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Vasoconstrictor Agents/metabolism
- Vasoconstrictor Agents/pharmacology
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Affiliation(s)
- Yuki Takazawa
- Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Vehaskari VM, Woods LL. Prenatal programming of hypertension: lessons from experimental models. J Am Soc Nephrol 2005; 16:2545-56. [PMID: 16049066 DOI: 10.1681/asn.2005030300] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- V Matti Vehaskari
- Department of Pediatrics, Division of Pediatric Nephrology, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA.
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24
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Ouyang X, Le TH, Roncal C, Gersch C, Herrera-Acosta J, Rodriguez-Iturbe B, Coffman TM, Johnson RJ, Mu W. Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice. Am J Physiol Renal Physiol 2005; 289:F902-10. [PMID: 15928210 DOI: 10.1152/ajprenal.00141.2005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
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Affiliation(s)
- Xiaosen Ouyang
- Division of Nephrology, Dept. of Medicine, Univ. of Florida, Gainesville, FL 32610, USA.
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25
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Racasan S, Braam B, Koomans HA, Joles JA. Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon. Am J Physiol Renal Physiol 2005; 288:F626-36. [PMID: 15547115 DOI: 10.1152/ajprenal.00314.2004] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The “programming hypothesis” proposes that an adverse perinatal milieu leads to adaptation that translates into cardiovascular disease in adulthood. The balance between nitric oxide (NO) and reactive oxygen species (ROS) is disturbed in cardiovascular diseases, including hypertension. Conceivably, this balance is also disturbed in pregnancy, altering the fetal environment; however, effects of perinatal manipulation of NO and ROS on adult blood pressure (BP) are unknown. In spontaneously hypertensive rats (SHR), NO availability is decreased and ROS are increased compared with normotensive Wistar-Kyoto rats, and, despite the genetic predisposition, the perinatal environment can modulate adult BP. Our hypothesis is that a disturbed NO-ROS balance in the SHR dam persistently affects BP in her offspring. Dietary supplements, which support NO formation and scavenge ROS, administered during pregnancy and lactation resulted in persistently lower BP for up to 48 wk in SHR offspring. The NO donor molsidomine and the superoxide dismutase mimic tempol-induced comparable effects. Specific inhibition of inducible nitric oxide synthase (NOS) reduces BP in adult SHR, suggesting that inducible NOS is predominantly a source of ROS in SHR. Indeed, inducible NOS inhibition in SHR dams persistently reduced BP in adult offspring. Persistent reductions in BP were accompanied by prevention of proteinuria in aged SHR. We propose that in SHR the known increase in ANG II type 1 receptor density during development leads to superoxide production, which enhances inducible NOS activity. The relative shortage of substrate and cofactors leads to uncoupling of inducible NOS, resulting in superoxide production, activating transcription factors that subsequently again increase inducible NOS expression. This vicious circle probably is perpetuated into adult life.
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Affiliation(s)
- Simona Racasan
- Dept. of Nephrology and Hypertension, F03.226, University Medical Ctr., PO Box 85500, 3508 GA Utrecht, The Netherlands
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Manning J, Vehaskari VM. Postnatal modulation of prenatally programmed hypertension by dietary Na and ACE inhibition. Am J Physiol Regul Integr Comp Physiol 2004; 288:R80-4. [PMID: 15458966 DOI: 10.1152/ajpregu.00309.2004] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Adult hypertension in the rat can be programmed experimentally by changes in intrauterine environment. The offspring typically do not become hypertensive until 6 to 8 wk of age, and recent evidence suggests that renal dysfunction may participate in the pathogenesis. The present study was based on the hypothesis that the window for programming extends to the postnatal period in the rat. Adult hypertension was induced by maternal low-protein diet during the second half of gestation. After being weaned at 3 wk, the offspring were exposed to one of the following regimens for the subsequent 3 wk: 1) low-Na diet, 2) standard Na diet, 3) high-Na diet, and 4) standard Na diet with enalapril. The pups were followed for 10 wk after discontinuation of the treatments. The brief exposure to low-Na diet or enalapril totally prevented the development of hypertension and the effect lasted throughout the observation period. The development of hyperreninemia, present in the standard Na group at 16 wk of age, was abolished in the low-Na and enalapril groups. Conversely, 3-wk exposure to high-Na diet increased the severity of the later hypertension and did not prevent the hyperreninemia. The findings suggest that there is a period of susceptibility during which prenatally programmed hypertension can be modulated postnatally, possibly coinciding with a critical stage in renal maturation.
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Affiliation(s)
- Jennifer Manning
- The Research Institute for Children, Department of Pediatrics, Louisianna State University Health Sciences Center, New Orleans, LA 70118, USA
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Racasan S, Braam B, van der Giezen DM, Goldschmeding R, Boer P, Koomans HA, Joles JA. Perinatal L-arginine and antioxidant supplements reduce adult blood pressure in spontaneously hypertensive rats. Hypertension 2004; 44:83-8. [PMID: 15184350 DOI: 10.1161/01.hyp.0000133251.40322.20] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Embryo cross-transplantation and cross-fostering between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) suggest that perinatal environment modulates the genetically determined phenotype. In SHR the balance between NO and reactive oxygen species (ROS) is disturbed. We hypothesized that increasing NO and diminishing ROS in perinatal life would ameliorate hypertension in adult SHR. Pregnant SHR and WKY and their offspring received l-arginine plus antioxidants (vitamin C, vitamin E, and taurine) during the last 2 weeks of pregnancy and then until either 4 or 8 weeks after birth. Systolic blood pressure (SBP) and urinary excretion of protein, nitrates (NO(x)), and thiobarbituric acid reactive substances (TBARS) were measured. At 48 weeks of age rats were euthanized for glomerular counts. Perinatal supplements reduced SBP persistently in SHR and prevented the SBP increase observed in aging WKY. Initially NO(x) excretion was lower and TBARS excretion higher in SHR than WKY. There was a direct effect on NO(x) excretion in supplemented pregnant SHR and their offspring, but no increase was observed after stopping the supplements. TBARS excretion was only depressed up to 14 weeks by the supplements despite persistent differences in SBP. Consistent effects on nephron number were absent. Mild proteinuria, present in control SHR at 48 weeks, was prevented in all supplemented rats. Perinatal supplementation of NO substrate and antioxidants results in persistent reduction of SBP and renal protection in SHR, although effects on NO(x) and TBARS were only transient. This suggests a critical role for perinatal pro- and antioxidant balance in programming BP later in life.
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Affiliation(s)
- Simona Racasan
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
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