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Devetzi M, Goulielmaki M, Khoury N, Spandidos DA, Sotiropoulou G, Christodoulou I, Zoumpourlis V. Genetically‑modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)‑based targeted therapy (Review). Int J Mol Med 2018; 41:1177-1186. [PMID: 29328364 PMCID: PMC5819898 DOI: 10.3892/ijmm.2018.3361] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/02/2018] [Indexed: 12/12/2022] Open
Abstract
The tissue kallikrein-kinin system (KKS) is an endogenous multiprotein metabolic cascade which is implicated in the homeostasis of the cardiovascular, renal and central nervous system. Human tissue kallikrein (KLK1) is a serine protease, component of the KKS that has been demonstrated to exert pleiotropic beneficial effects in protection from tissue injury through its anti-inflammatory, anti-apoptotic, anti-fibrotic and anti-oxidative actions. Mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) constitute populations of well-characterized, readily obtainable multipotent cells with special immunomodulatory, migratory and paracrine properties rendering them appealing potential therapeutics in experimental animal models of various diseases. Genetic modification enhances their inherent properties. MSCs or EPCs are competent cellular vehicles for drug and/or gene delivery in the targeted treatment of diseases. KLK1 gene delivery using adenoviral vectors or KLK1 protein infusion into injured tissues of animal models has provided particularly encouraging results in attenuating or reversing myocardial, renal and cerebrovascular ischemic phenotype and tissue damage, thus paving the way for the administration of genetically modified MSCs or EPCs with the human tissue KLK1 gene. Engraftment of KLK1-modified MSCs and/or KLK1-modified EPCs resulted in advanced beneficial outcome regarding heart and kidney protection and recovery from ischemic insults. Collectively, findings from pre-clinical studies raise the possibility that tissue KLK1 may be a novel future therapeutic target in the treatment of a wide range of cardiovascular, cerebrovascular and renal disorders.
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Affiliation(s)
- Marina Devetzi
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Goulielmaki
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Nicolas Khoury
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | | | - Ioannis Christodoulou
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
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He Z, Zhang X, Chen C, Wen Z, Hoopes SL, Zeldin DC, Wang DW. Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II. Cardiovasc Res 2015; 105:304-17. [PMID: 25618409 DOI: 10.1093/cvr/cvv018] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
AIMS Cardiac remodelling is one of the key pathological changes that occur with cardiovascular disease. Previous studies have demonstrated the beneficial effects of CYP2J2 expression on cardiac injury. In the present study, we investigated the effects of cardiomyocyte-specific CYP2J2 expression and EET treatment on angiotensin II-induced cardiac remodelling and sought to determine the underlying molecular mechanisms involved in this process. METHODS AND RESULTS Eight-week-old mice with cardiomyocyte-specific CYP2J2 expression (αMHC-CYP2J2-Tr) and wild-type (WT) control mice were treated with Ang-II. Ang-II treatment of WT mice induced changes in heart morphology, cardiac hypertrophy and dysfunction, as well as collagen accumulation; however, cardiomyocyte-specific expression of CYP2J2 attenuated these effects. The cardioprotective effects observed in α-MHC-CYP2J2-Tr mice were associated with peroxisome proliferator-activated receptor (PPAR)-γ activation, reduced oxidative stress, reduced NF-κB p65 nuclear translocation, and inhibition of TGF-β1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-γ antagonist GW9662. In in vitro studies, 11,12-EET(1 μmol/L) treatment attenuated cardiomyocyte hypertrophy and remodelling-related protein (collagen I, TGF-β1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-κB pathway via PPAR-γ activation. Furthermore, conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-β1/smad pathway. CONCLUSION Cardiomyocyte-specific expression of CYP2J2 or treatment with EETs protects against cardiac remodelling by attenuating oxidative stress-mediated NF-κBp65 nuclear translocation via PPAR-γ activation.
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Affiliation(s)
- Zuowen He
- Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Avenue, Wuhan 430030, P. R. China
| | - Xu Zhang
- Department of Physiology, Tianjin Medical University, Tianjin, P. R. China
| | - Chen Chen
- Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Avenue, Wuhan 430030, P. R. China
| | - Zheng Wen
- Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Avenue, Wuhan 430030, P. R. China
| | - Samantha L Hoopes
- Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
| | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
| | - Dao Wen Wang
- Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Avenue, Wuhan 430030, P. R. China
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Chao J, Bledsoe G, Chao L. Kallikrein-kinin in stem cell therapy. World J Stem Cells 2014; 6:448-457. [PMID: 25258666 PMCID: PMC4172673 DOI: 10.4252/wjsc.v6.i4.448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/27/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.
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Chao J, Bledsoe G, Chao L. Tissue kallikrein-kinin therapy in hypertension and organ damage. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2014; 69:37-57. [PMID: 25130039 DOI: 10.1007/978-3-319-06683-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Tissue kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, tissue kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and gamma-epithelial Na channel. The tissue kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment tissue kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.
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Girolami JP, Blaes N, Bouby N, Alhenc-Gelas F. Genetic manipulation and genetic variation of the kallikrein-kinin system: impact on cardiovascular and renal diseases. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2014; 69:145-196. [PMID: 25130042 DOI: 10.1007/978-3-319-06683-7_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Genetic manipulation of the kallikrein-kinin system (KKS) in mice, with either gain or loss of function, and study of human genetic variability in KKS components which has been well documented at the phenotypic and genomic level, have allowed recognizing the physiological role of KKS in health and in disease. This role has been especially documented in the cardiovascular system and the kidney. Kinins are produced at slow rate in most organs in resting condition and/or inactivated quickly. Yet the KKS is involved in arterial function and in renal tubular function. In several pathological situations, kinin production increases, kinin receptor synthesis is upregulated, and kinins play an important role, whether beneficial or detrimental, in disease outcome. In the setting of ischemic, diabetic or hemodynamic aggression, kinin release by tissue kallikrein protects against organ damage, through B2 and/or B1 bradykinin receptor activation, depending on organ and disease. This has been well documented for the ischemic or diabetic heart, kidney and skeletal muscle, where KKS activity reduces oxidative stress, limits necrosis or fibrosis and promotes angiogenesis. On the other hand, in some pathological situations where plasma prekallikrein is inappropriately activated, excess kinin release in local or systemic circulation is detrimental, through oedema or hypotension. Putative therapeutic application of these clinical and experimental findings through current pharmacological development is discussed in the chapter.
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Abstract
The renin-angiotensin system (RAS) constitutes one of the most important hormonal systems in the physiological regulation of blood pressure through renal and nonrenal mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, including kidney injury, and blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or blockade of the angiotensin type 1 receptor (AT1R) by selective antagonists constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS within the kidney and other tissues that the system is actually composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, water intake, sodium retention, and other mechanisms to maintain blood pressure, as well as increase oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the nonclassical RAS composed primarily of the AngII/Ang III-AT2R pathway and the ACE2-Ang-(1-7)-AT7R axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and reduced oxidative stress. Moreover, increasing evidence suggests that these non-classical RAS components contribute to the therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury, as well as contribute to normal renal function.
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Affiliation(s)
- Mark C Chappell
- The Hypertension & Vascular Disease Center, Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
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Katsi V, Katsimichas T, Pittaras A, Grassos C, Katsimichas A, Tousoulis D, Stefanadis C, Kallikazaros I. Hypertension and bradykinin. Cardiovasc Endocrinol 2012; 1:24-30. [DOI: 10.1097/xce.0b013e328357a94c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Xiao B, Li X, Yan J, Yu X, Yang G, Xiao X, Voltz JW, Zeldin DC, Wang DW. Overexpression of cytochrome P450 epoxygenases prevents development of hypertension in spontaneously hypertensive rats by enhancing atrial natriuretic peptide. J Pharmacol Exp Ther 2010; 334:784-94. [PMID: 20501636 PMCID: PMC2939659 DOI: 10.1124/jpet.110.167510] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Accepted: 05/24/2010] [Indexed: 11/22/2022] Open
Abstract
Cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) exert well recognized vasodilatory, diuretic, and tubular fluid-electrolyte transport actions that are predictive of a hypotensive effect. The study sought to determine the improvement of hypertension and cardiac function by overexpressing P450 epoxygenases in vivo. Long-term expression of CYP102 F87V or CYP2J2 in spontaneously hypertensive rats (SHR) was mediated by using a type 8 recombinant adeno-associated virus (rAAV8) vector. Hemodynamics was measured by a Millar Instruments, Inc. (Houston, TX) microtransducer catheter, and atrial natriuretic peptide (ANP) mRNA levels were tested by real-time polymerase chain reaction. Results showed that urinary excretion of 14,15-EET was increased at 2 and 6 months after injection with rAAV-CYP102 F87V and rAAV-CYP2J2 compared with controls (p < 0.05). During the course of the 6-month study, systolic blood pressure significantly decreased in P450 epoxygenase-treated rats, but the CYP2J2-specific inhibitor C26 blocked rAAV-CYP2J2-induced hypotension and the increase in EET production. Cardiac output was improved by P450 epoxygenase expression at 6 months (p < 0.05). Furthermore, cardiac collagen content was reduced in P450 epoxygenase-treated rats. ANP mRNA levels were up-regulated 6- to 14-fold in the myocardium, and ANP expression was significantly increased in both myocardium and plasma in P450 epoxygenase-treated rats. However, epidermal growth factor (EGF) receptor antagonist 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG-1478) significantly attenuated the increase in the EET-induced expression of ANP in vitro. These data indicate that overexpression of P450 epoxygenases attenuates the development of hypertension and improves cardiac function in SHR, and that these effects may be mediated, at least in part, by ANP via activating EGF receptor.
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MESH Headings
- 8,11,14-Eicosatrienoic Acid/analogs & derivatives
- 8,11,14-Eicosatrienoic Acid/metabolism
- 8,11,14-Eicosatrienoic Acid/urine
- Adenoviridae/genetics
- Animals
- Aorta, Thoracic/drug effects
- Atrial Natriuretic Factor/genetics
- Atrial Natriuretic Factor/physiology
- Blood Pressure/genetics
- Blood Pressure/physiology
- Blotting, Western
- Cytochrome P-450 CYP2J2
- Cytochrome P-450 Enzyme System/biosynthesis
- Cytochrome P-450 Enzyme System/genetics
- Cytochrome P-450 Enzyme System/physiology
- Genetic Vectors
- Heart Function Tests
- Hemodynamics/genetics
- Hemodynamics/physiology
- Hypertension/genetics
- Hypertension/physiopathology
- Immunohistochemistry
- In Vitro Techniques
- Male
- Muscle Relaxation/drug effects
- Muscle, Smooth, Vascular/drug effects
- Myocytes, Cardiac/drug effects
- Rats
- Rats, Inbred SHR
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Bin Xiao
- The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Chao J, Shen B, Gao L, Xia CF, Bledsoe G, Chao L. Tissue kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing. Biol Chem 2010; 391:345-55. [PMID: 20180644 DOI: 10.1515/bc.2010.042] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tissue kallikrein (KLK1) processes low-molecular weight kininogen to produce vasoactive kinins, which exert biological functions via kinin receptor signaling. Using various delivery approaches, we have demonstrated that tissue kallikrein through kinin B2 receptor signaling exhibits a wide spectrum of beneficial effects by reducing cardiac and renal injuries, restenosis and ischemic stroke, and by promoting angiogenesis and skin wound healing, independent of blood pressure reduction. Protection by tissue kallikrein in oxidative organ damage is attributed to the inhibition of apoptosis, inflammation, hypertrophy and fibrosis. Tissue kallikrein also enhances neovascularization in ischemic heart and limb. Moreover, tissue kallikrein/kinin infusion not only prevents but also reverses kidney injury, inflammation and fibrosis in salt-induced hypertensive rats. Furthermore, there is a wide time window for kallikrein administration in protection against ischemic brain infarction, as delayed kallikrein infusion for 24 h after cerebral ischemia in rats is effective in reducing neurological deficits, infarct size, apoptosis and inflammation. Importantly, in the clinical setting, human tissue kallikrein has been proven to be effective in the treatment of patients with acute brain infarction when injected within 48 h after stroke onset. Finally, kallikrein promotes skin wound healing and keratinocyte migration by direct activation of protease-activated receptor 1.
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Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, 29425, USA.
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Katori M, Majima M. A Novel Category of Anti-Hypertensive Drugs for Treating Salt-Sensitive Hypertension on the Basis of a New Development Concept. Pharmaceuticals (Basel) 2010; 3:59-109. [PMID: 27713243 PMCID: PMC3991021 DOI: 10.3390/ph3010059] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2009] [Revised: 12/24/2009] [Accepted: 01/06/2010] [Indexed: 12/20/2022] Open
Abstract
Terrestrial animals must conserve water and NaCl to survive dry environments. The kidney reabsorbs 95% of the sodium filtered from the glomeruli before sodium reaches the distal connecting tubules. Excess sodium intake requires the renal kallikrein-kinin system for additional excretion. Renal kallikrein is secreted from the distal connecting tubule cells of the kidney, and its substrates, low molecular kininogen, from the principal cells of the cortical collecting ducts (CD). Formed kinins inhibit reabsorption of NaCl through bradykinin (BK)-B₂ receptors, localized along the CD. Degradation pathway of BK by kinin-destroying enzymes in urine differs completely from that in plasma, so that ACE inhibitors are ineffective. Urinary BK is destroyed mainly by a carboxypeptidase-Y-like exopeptidase (CPY) and partly by a neutral endopeptidase (NEP). Inhibitors of CPY and NEP, ebelactone B and poststatin, respectively, were found. Renal kallikrein secretion is accelerated by potassium and ATP-sensitive potassium (KATP) channel blockers, such as PNU-37883A. Ebelactone B prevents DOCA-salt hypertension in rats. Only high salt intake causes hypertension in animals deficient in BK-B2 receptors, tissue kallikrein, or kininogen. Hypertensive patients, and spontaneously hypertensive rats, excrete less kallikrein than normal subjects, irrespective of races, and become salt-sensitive. Ebelactone B, poststatin, and KATP channel blockers could become novel antihypertensive drugs by increase in urinary kinin levels. Roles of kinin in cardiovascular diseases were discussed.
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Affiliation(s)
- Makoto Katori
- Department of Pharmacology, School of Medicine, Kitasato University, Sagamihara, Kanagawa 228-8555, Japan.
| | - Masataka Majima
- Department of Pharmacology, School of Medicine, Kitasato University, Sagamihara, Kanagawa 228-8555, Japan
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Griol-Charhbili V, Sabbah L, Colucci J, Vincent MP, Baudrie V, Laude D, Elghozi JL, Bruneval P, Picard N, Meneton P, Alhenc-Gelas F, Richer C. Tissue kallikrein deficiency and renovascular hypertension in the mouse. Am J Physiol Regul Integr Comp Physiol 2009; 296:R1385-91. [DOI: 10.1152/ajpregu.90411.2008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The kallikrein kinin system (KKS) is involved in arterial and renal functions. It may have an antihypertensive effect in both essential and secondary forms of hypertension. The role of the KKS in the development of two-kidneys, one-clip (2K1C) hypertension, a high-renin model, was investigated in mice rendered deficient in tissue kallikrein (TK) and kinins by TK gene inactivation (TK−/−) and in their wild-type littermates (TK+/+). Four weeks after clipping the renal artery, blood flow was reduced in the clipped kidney (2K1C-TK+/+: −90%, 2K1C-TK−/−: −93% vs. sham-operated mice), and the kidney mass had also decreased (2K1C-TK+/+: −65%, 2K1C-TK−/−: −66%), whereas in the unclipped kidney, blood flow (2K1C-TK+/+: +19%, 2K1C-TK−/−: +17%) and kidney mass (2K1C-TK+/+: +32%, 2K1C-TK−/−: +30%) had both increased. The plasma renin concentration (2K1C-TK+/+: +78%, 2K1C-TK−/−: +65%) and renal renin content of the clipped kidney (2K1C-TK+/+: +58%, 2K1C-TK−/−: +65%) had increased significantly. There was no difference for these parameters between 2K1C-TK+/+ and 2K1C-TK−/− mice. Blood pressure monitored by telemetry and by plethysmography, rose immediately after clipping in both genotypes, and reached similar levels (2K1C-TK+/+: +24%, 2K1C-TK−/−: +21%). 2K1C-TK+/+ and 2K1C-TK−/− mice developed similar concentric left ventricular hypertrophy (+24% and +17%, respectively) with normal cardiac function. These findings suggest that in the context of chronic unilateral reduction in renal blood flow, TK and kinins do not influence the trophicity of kidneys, the synthesis and secretion of renin, blood pressure increase, and cardiac remodeling due to renin angiotensin system activation.
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Abstract
Since kallikrein was discovered as a vasodilatory substance in human urine, the kallikrein-kinin system (KKS) has been considered to play a physiological role in controlling blood pressure. Gene targeting experiments in mice in which the KKS has been inactivated to varying degrees have, however, questioned this role, because basal blood pressures are not altered. Rather, these experiments have shown that the KKS has a different and important role in preventing changes associated with normal senescence in mice, and in reducing the nephropathy and accelerated senescence-associated phenotypes induced in mice by diabetes. Other experiments have shown that the KKS suppresses mitochondrial respiration, partly by nitric oxide and prostaglandins, and that this suppression may be a key to understanding how the KKS influences senescence-related diseases. Here we review the logical progression and experimental data leading to these conclusions, and discuss their relevance to human conditions.
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Affiliation(s)
- Masao Kakoki
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
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Gava AL, Peotta VA, Cabral AM, Vasquez EC, Meyrelles SS. Overexpression of eNOS prevents the development of renovascular hypertension in mice. Can J Physiol Pharmacol 2008; 86:458-64. [PMID: 18641695 DOI: 10.1139/y08-044] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Gene therapy has become an important tool for understanding several cardiovascular diseases. In the present study we investigated the effects of endothelial nitric oxide synthase (eNOS) overexpression on renovascular hypertension. Experiments were carried out in C57BL/6 mice randomly assigned to either a two-kidney one-clip (2K1C) hypertension group or a sham-operated group. At the same time surgery was carried out, both 2K1C and sham mice received an intravenous injection of recombinant adenovirus expressing the functional gene eNOS or the reporter gene beta-galactosidase (beta-gal). Fourteen days later, arterial pressure, baroreflex sensitivity, and cardiac sympathetic and parasympathetic tone were evaluated in conscious mice. Measurement of mean arterial pressure showed arterial hypertension in 2K1C-betagal mice compared with sham-betagal mice (121 +/- 3 vs. 96 +/- 2 mm Hg, p < 0.01), which was prevented by eNOS overexpression (2K1C-eNOS 100 +/- 4 vs. sham-eNOS 99 +/- 3 mm Hg). Linear regression analysis of the reflex tachycardia response to sodium nitroprusside-induced hypotension showed that baroreflex sensitivity was significantly attenuated in 2K1C-betagal mice (5.8 +/- 0.5 vs. sham-betagal 8.0 +/- 0.8 beats.min-1 x mm Hg-1, p < 0.05), but this decrease was not prevented by eNOS overexpression (2K1C-eNOS 7.2 +/- 0.5 vs. sham-eNOS 8.8 +/- 0.7 beats x min-1 x mm Hg-1, p < 0.05). The cardiac sympathetic tone was augmented and the vagal tone was reduced in 2K1C-betagal (152 +/- 17 and 45 +/- 12 beats.min-1, respectively) compared with sham-betagal mice (112 +/- 6 and 89 +/- 7 beats.min-1, respectively), and similar results were observed in 2K1C-eNOS mice compared with sham-eNOS. The data indicate that eNOS overexpression was able to prevent the development of 2K1C renovascular hypertension in mice, without affecting other characteristic cardiovascular dysfunctions.
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Affiliation(s)
- Agata L Gava
- Laboratory of Transgenes and Cardiovascular Control, Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Avenida. Marechal Campos 1468, Vitoria, ES 29043-900, Brazil
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Pawluczyk IZA, Tan EKC, Lodwick D, Harris KPG. Kallikrein gene ‘knock-down’ by small interfering RNA transfection induces a profibrotic phenotype in rat mesangial cells. J Hypertens 2008; 26:93-101. [DOI: 10.1097/hjh.0b013e3282f0ca68] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Zhao W, Wang L, Lu X, Yang W, Huang J, Chen S, Gu D. A coding polymorphism of the kallikrein 1 gene is associated with essential hypertension: a tagging SNP-based association study in a Chinese Han population. J Hypertens 2007; 25:1821-7. [PMID: 17762646 DOI: 10.1097/hjh.0b013e328244e119] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the association between common variants in the human tissue kallikrein 1 (KLK1) gene and susceptibility to essential hypertension in Chinese Han. METHODS A tagging single nucleotide polymorphism (tSNP) approach was used for a case-control study in 2411 patients with essential hypertension and 2348 controls. All DNA samples and clinical data were collected from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). RESULTS Based on the HapMap data of Han Chinese in Beijing (CHB) population, two non-synonymous polymorphisms, namely rs5517 (Glu162Lys) and rs5516 (Gln121Glu), were selected as tSNPs which could efficiently tag eight SNPs of the KLK1 gene with R larger than 90% for both haplotypes and single locus. Significant differences were found between groups for frequencies of rs5517 A allele (42.48% in cases versus 39.32% in controls, P=0.0019) and AA genotype [adjusted odds ratio (OR)=1.25 for AA versus AG/GG, P=0.0067]. The haplotype composed of the rs5517 A and rs5516 G allele significantly increased the risk of hypertension, with adjusted OR of 1.12 [95% confidence interval (CI), 1.04-1.28, P=0.0377] when compared with the common haplotype G-C. Diplotype analysis also showed a significant association between the diplotype of AG-AC and essential hypertension (OR=1.34, 95% CI, 1.07-1.68, P=0.0096). CONCLUSIONS The present study suggested that rs5517 in the KLK1 gene was significantly associated with essential hypertension in a Chinese Han population.
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Affiliation(s)
- Weiyan Zhao
- Department of Evidence Based Medicine and Division of Population Genetics, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Madeddu P, Emanueli C, El-Dahr S. Mechanisms of Disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling. ACTA ACUST UNITED AC 2007; 3:208-21. [PMID: 17389890 DOI: 10.1038/ncpneph0444] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2006] [Accepted: 01/16/2007] [Indexed: 11/09/2022]
Abstract
The pathogenesis of arterial hypertension often involves a rise in systemic vascular resistance (vasoconstriction and vascular remodeling) and impairment of salt excretion in the kidney (inappropriate salt retention despite elevated blood pressure). Experimental and clinical evidence implicate an imbalance between endogenous vasoconstrictor and vasodilator systems in the development and maintenance of hypertension. Kinins (bradykinin and lys-bradykinin) are endogenous vasodilators and natriuretic peptides known best for their ability to antagonize angiotensin-induced vasoconstriction and sodium retention. In humans, angiotensin-converting enzyme inhibitors, a potent class of antihypertensive agents, lower blood pressure at least partially by favoring enhanced kinin accumulation in plasma and target tissues. The beneficial actions of kinins in renal and cardiovascular disease are largely mediated by nitric oxide and prostaglandins, and extend beyond their recognized role in lowering blood pressure to include cardioprotection and nephroprotection. This article is a review of exciting, recently generated genetic, biochemical and clinical data from studies that have examined the importance of the tissue kallikrein-kinin system in protection from hypertension, vascular remodeling and renal fibrosis. Development of novel therapeutic approaches to bolster kinin activity in the vascular wall and in specific compartments in the kidney might be a highly effective strategy for the treatment of hypertension and its complications, including cardiac hypertrophy and renal failure.
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Affiliation(s)
- Paolo Madeddu
- Experimental Cardiovascular Medicine, Bristol Heart Institute, Bristol University, Bristol, UK.
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Toda N, Ayajiki K, Okamura T. Interaction of endothelial nitric oxide and angiotensin in the circulation. Pharmacol Rev 2007; 59:54-87. [PMID: 17329548 DOI: 10.1124/pr.59.1.2] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Discovery of the unexpected intercellular messenger and transmitter nitric oxide (NO) was the highlight of highly competitive investigations to identify the nature of endothelium-derived relaxing factor. This labile, gaseous molecule plays obligatory roles as one of the most promising physiological regulators in cardiovascular function. Its biological effects include vasodilatation, increased regional blood perfusion, lowering of systemic blood pressure, and antithrombosis and anti-atherosclerosis effects, which counteract the vascular actions of endogenous angiotensin (ANG) II. Interactions of these vasodilator and vasoconstrictor substances in the circulation have been a topic that has drawn the special interest of both cardiovascular researchers and clinicians. Therapeutic agents that inhibit the synthesis and action of ANG II are widely accepted to be essential in treating circulatory and metabolic dysfunctions, including hypertension and diabetes mellitus, and increased availability of NO is one of the most important pharmacological mechanisms underlying their beneficial actions. ANG II provokes vascular actions through various receptor subtypes (AT1, AT2, and AT4), which are differently involved in NO synthesis and actions. ANG II and its derivatives, ANG III, ANG IV, and ANG-(1-7), alter vascular contractility with different mechanisms of action in relation to NO. This review article summarizes information concerning advances in research on interactions between NO and ANG in reference to ANG receptor subtypes, radical oxygen species, particularly superoxide anions, ANG-converting enzyme inhibitors, and ANG receptor blockers in patients with cardiovascular disease, healthy individuals, and experimental animals. Interactions of ANG and endothelium-derived relaxing factor other than NO, such as prostaglandin I2 and endothelium-derived hyperpolarizing factor, are also described.
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Affiliation(s)
- Noboru Toda
- Department of Pharmacology, Shiga University of Medical Science, Seta, Otsu, Japan.
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18
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Abstract
In this review, we outline the application and contribution of transgenic technology to establishing the genetic basis of blood pressure regulation and its dysfunction. Apart from a small number of examples where high blood pressure is the result of single gene mutation, essential hypertension is the sum of interactions between multiple environmental and genetic factors. Candidate genes can be identified by a variety of means including linkage analysis, quantitative trait locus analysis, association studies, and genome-wide scans. To test the validity of candidate genes, it is valuable to model hypertension in laboratory animals. Animal models generated through selective breeding strategies are often complex, and the underlying mechanism of hypertension is not clear. A complementary strategy has been the use of transgenic technology. Here one gene can be selectively, tissue specifically, or developmentally overexpressed, knocked down, or knocked out. Although resulting phenotypes may still be complicated, the underlying genetic perturbation is a starting point for identifying interactions that lead to hypertension. We recognize that the development and maintenance of hypertension may involve many systems including the vascular, cardiac, and central nervous systems. However, given the central role of the kidney in normal and abnormal blood pressure regulation, we intend to limit our review to models with a broadly renal perspective.
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Affiliation(s)
- Linda J Mullins
- Molecular Physiology Laboratory, Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
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19
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Xia CF, Yin H, Yao YY, Borlongan CV, Chao L, Chao J. Kallikrein protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. Hum Gene Ther 2006; 17:206-19. [PMID: 16454654 DOI: 10.1089/hum.2006.17.206] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Stroke-induced neurological deficits and mortality are often associated with timing of treatment after the onset of stroke. We showed that local delivery of the human tissue kallikrein gene into rat brain immediately after middle cerebral artery occlusion (MCAO) exerts neuroprotection. In this study, we investigated the effect of systemic delivery of the kallikrein gene 8 hr after MCAO. Expression of recombinant human tissue kallikrein after gene transfer was identified in the ischemic brain region and blood vessels. Intravenous injection of adenovirus encoding the kallikrein gene significantly reduced neurological deficit scores 2 and 7 days after gene transfer. Kallikrein gene transfer also reduced ischemia-reperfusion (I/R)-induced cerebral infarction and promoted the survival and migration of glial cells from penumbra to the ischemic core from 3 to 14 days after gene delivery. Kallikrein reduced I/R-induced apoptosis of neuronal cells and inhibited inflammatory cell accumulation in the ischemic brain. These effects were blocked by the kinin B2 receptor antagonist icatibant. In addition, kallikrein enhanced angiogenesis and promoted neurogenesis after I/R and the stimulatory effect of kinin on neuronal cell proliferation was confirmed in primary cultured neuronal cells. The protective effects of kallikrein, through the kinin B2 receptor, were accompanied by increased cerebral nitric oxide and Bcl-2 levels, Akt phosphorylation, and reduced NAD(P)H oxidase activity, superoxide production, Bax levels, and caspase-3 activity. These results indicate that delayed systemic administration of the kallikrein gene after onset of stroke protects against ischemic brain injury by inhibiting apoptosis and inflammation and by promoting angiogenesis and neurogenesis.
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Affiliation(s)
- Chun-Fang Xia
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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20
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Moniwa N, Agata J, Hagiwara M, Ura N, Shimamoto K. The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP). Biol Chem 2006; 387:203-9. [PMID: 16497153 DOI: 10.1515/bc.2006.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
An angiotensin-converting enzyme inhibitor (ACE-I) reduces cardiac remodeling and a bradykinin B2 receptor (B2R) antagonist partially abolishes this ACE-I effect. However, bradykinin has two different types of receptor, the B1 receptor (B1R) and B2R. Although B1R is induced under several pathological conditions, including hypertension, the role of cardiac B1R in hypertension is not clear. We therefore investigated the role of cardiac B1R in stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. The B1R mRNA expression level in the heart was significantly higher in SHR-SP than in WKY rats. Chronic infusion of a B1R antagonist for 4 weeks significantly elevated blood pressure and left-ventricular weight of SHR-SP. Morphological analysis indicated that cardiomyocyte size and cardiac fibrosis significantly increased after administration of the B1R antagonist. The phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, and JNK, was significantly increased in the hearts of SHR-SP rats receiving the B1R antagonist. The TGF-β1 expression level was significantly increased in SHR-SP rats treated with the B1R antagonist compared to that in WKY rats. The B1R antagonist significantly increased phosphorylation of Thr495 in endothelial nitric oxide synthase (eNOS), which is an inhibitory site of eNOS. These results suggest that the role of B1R in the heart may be attenuation of cardiac remodeling via inhibition of the expression of MAP kinases and TGF-β1 through an increase in eNOS activity in a hypertensive condition.
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Affiliation(s)
- Norihito Moniwa
- Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
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21
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Xia CF, Yin H, Yao YY, Borlongan CV, Chao L, Chao J. Kallikrein Protects Against Ischemic Stroke by Inhibiting Apoptosis and Inflammation and Promoting Angiogenesis and Neurogenesis. Hum Gene Ther 2006. [DOI: 10.1089/hum.2006.17.ft-178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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Chao J, Bledsoe G, Yin H, Chao L. The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction. Biol Chem 2006; 387:665-75. [PMID: 16800727 DOI: 10.1515/bc.2006.085] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Tissue kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human tissue kallikrein or kinin B2 receptor are permanently hypotensive, and somatic kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, tissue kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that tissue kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.
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Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
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23
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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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24
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Couture R, Girolami JP. Putative roles of kinin receptors in the therapeutic effects of angiotensin 1-converting enzyme inhibitors in diabetes mellitus. Eur J Pharmacol 2005; 500:467-85. [PMID: 15464053 DOI: 10.1016/j.ejphar.2004.07.045] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2004] [Indexed: 02/07/2023]
Abstract
The role of endogenous kinins and their receptors in diabetes mellitus is being confirmed with the recent developments of molecular and genetic animal models. Compelling evidence suggests that the kinin B(2) receptor is organ-protective and partakes to the therapeutic effects of angiotensin 1-converting enzyme inhibitors (ACEI) and angiotensin AT(1) receptor antagonists. Benefits derive primarily from vasodilatory, antihypertensive, antiproliferative, antihypertrophic, antifibrotic, antithrombotic and antioxidant properties of kinin B(2) receptor activation. Mechanisms include the formation of nitric oxide and prostacyclin and the inhibition of NAD(P)H oxidase activity involving classical and novel signalling pathways. Kinin B(2) receptor also ameliorates insulin resistance by increasing glucose uptake and supply, and by inducing glucose transporter-4 translocation either directly or through phosphorylation of insulin receptor. The kinin B(1) receptor, which is induced by the cytokine network, growth factors and hyperglycaemia, mediates hyperalgesia, vascular hyperpermeability and leukocytes infiltration in diabetic animals. However, emerging data highlight reno- and cardio-protective effects mediated by kinin B(1) receptor under chronic ACEI therapy in diabetes mellitus. Thus, the Janus-faced of kinin receptors needs to be taken into account in future drug development. For instance, locally acting kinin B(1)/B(2) receptor agonists if used in a safe therapeutic window may represent a more rationale strategy in the prevention and management of diabetic complications. Because kinin B(2) receptor antagonists may further increase insulin resistance, the persisting dogma that restricts the development of kinin receptor analogues to antagonists (that is still relevant to abrogate pain and inflammation) needs to be revisited.
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Affiliation(s)
- Réjean Couture
- Département de Physiologie, Faculté de Médecine, Université de Montréal, C.P. 6128, Succursale centre-ville, Montréal, Québec, Canada H3C 3J7.
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25
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Abstract
Tissue kallikrein, a serine proteinase, produces the potent vasodilator kinin peptide from kininogen substrate. The levels of tissue kallikrein are reduced in humans and animal models with hypertension, cardiovascular and renal disease. Using transgenic and somatic gene transfer approaches, we investigated the role of the tissue kallikrein-kinin system in cardiovascular, renal and central nervous systems. A single injection of the human tissue kallikrein gene in plasmid DNA or an adenoviral vector resulted in a prolonged reduction of blood pressure and attenuation of hypertrophy and fibrosis in the heart and kidney of several hypertensive animal models. Furthermore, enhanced kallikrein-kinin levels after gene transfer exerted beneficial effects, with protection against cardiac remodelling, renal injuries, restenosis, cerebral infarction and neurological deficits in normotensive animal models without haemodynamic effects, indicating direct actions of kallikrein independent of its ability to lower blood pressure. The effects of kallikrein were mediated by the kinin B2 receptor, as the specific B2 receptor antagonist icatibant abolished the actions of kallikrein. Moreover, kallikrein-kinin exhibited pleiotropic effects by inhibiting apoptosis, inflammation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in the heart, kidney, brain and blood vessel. Exogenous administration of kallikrein also led to increased nitric oxide (NO)/cGMP and cAMP levels, and reduced NAD(P)H oxidase activities, superoxide formation and pro-inflammatory cytokine levels. These results indicate a novel role of kallikrein-kinin through the kinin B2 receptor as an antioxidant and anti-inflammatory agent in protection against stroke, cardiovascular and renal disease, and may uncover new drug targets for the prevention and treatment of heart failure, vascular injury, end-stage renal disease and stroke in humans.
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Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
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26
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Montanari D, Yin H, Dobrzynski E, Agata J, Yoshida H, Chao J, Chao L. Kallikrein gene delivery improves serum glucose and lipid profiles and cardiac function in streptozotocin-induced diabetic rats. Diabetes 2005; 54:1573-80. [PMID: 15855348 DOI: 10.2337/diabetes.54.5.1573] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We investigated the role of the kallikrein-kinin system in cardiac function and glucose utilization in the streptozotocin (STZ)-induced diabetic rat model using a gene transfer approach. Adenovirus harboring the human tissue kallikrein gene was administered to rats by intravenous injection at 1 week after STZ treatment. Human kallikrein transgene expression was detected in the serum and urine of STZ-induced diabetic rats after gene transfer. Kallikrein gene delivery significantly reduced blood glucose levels and cardiac glycogen accumulation in STZ-induced diabetic rats. Kallikrein gene transfer also significantly attenuated elevated plasma triglyceride and cholesterol levels, food and water intake, and loss of body weight gain, epididymal fat pad, and gastrocnemius muscle weight in STZ-induced diabetic rats. However, these effects were blocked by icatibant, a kinin B2 receptor antagonist. Cardiac function was significantly improved after kallikrein gene transfer as evidenced by increased cardiac output and +/-delta P/delta t (maximum speed of contraction/relaxation), along with elevated cardiac sarco(endo)plasmic reticulum (Ca2+ + Mg2+)-ATPase (SERCA)-2a, phosphorylated phospholamban, NOx and cAMP levels, and GLUT4 translocation into plasma membranes of cardiac and skeletal muscle. Kallikrein gene delivery also increased Akt and glycogen synthase kinase (GSK)-3beta phosphorylation, resulting in decreased GSK-3beta activity in the heart. These results indicate that kallikrein through kinin formation protects against diabetic cardiomyopathy by improving cardiac function and promoting glucose utilization and lipid metabolism.
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Affiliation(s)
- David Montanari
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425-2211, USA
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27
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Passaglio KT, Baltatu O, Machado RP, dos Reis AM, Pesquero JB, Bader M, Santos RAS. Altered renal response to acute volume expansion in transgenic rats harboring the human tissue kallikrein gene. ACTA ACUST UNITED AC 2005; 124:127-35. [PMID: 15544850 DOI: 10.1016/j.regpep.2004.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2004] [Accepted: 07/02/2004] [Indexed: 10/26/2022]
Abstract
The renal response to acute volume expansion was investigated in transgenic (TGR) rats harboring the human tissue kallikrein gene. After a primer injection of 0.9% NaCl (3 ml/100 g, i.v), Sprague-Dawley (SD) or TGR rats received a continuous infusion of 0.9% NaCl (15 microl/100 g/min, i.a.) through a catheter placed into the carotid artery. Acute volume expansion was produced by a second injection of 0.9% NaCl (2 ml/100 g, i.v.) 65 min after the first injection. Plasma vasopressin (AVP) and atrial natriuretic peptide (ANP) concentration was measured before and within 10 min of volume expansion. TGR animals presented a blunted response to acute volume expansion evidenced by an attenuated increase in total and fractional water and sodium excretion. Before or after volume expansion, plasma AVP and ANP did not differ between SD and TGR. Pre-treatment with the BK-B2 antagonist HOE-140 (7.5 microg/100 g. i.a) partially improved the renal response of TGRs and severely blunted the response in SD rats. These data show that TGR (hKLK1) rats have an impaired renal response to acute volume expansion that can not be accounted for by changes in the release of AVP or ANP.
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Affiliation(s)
- Kátia T Passaglio
- Laboratório de Hipertensão, Instituto de Ciências Biológicas and Laboratório de Endocrinologia, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627, 31270-901, Belo Horizonte, Brazil
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Chen LG, Wang ZR, Wan CM, Xiao J, Guo L, Guo HL, Cornélissen G, Halberg F. Circadian renal rhythms influenced by implanted encapsulated hANP-producing cells in Goldblatt hypertensive rats. Gene Ther 2004; 11:1515-22. [PMID: 15284836 DOI: 10.1038/sj.gt.3302330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Renal excretion in experimental hypertensive rats implanted with encapsulated human atrial natriuretic peptide (hANP)-producing cells is circadian periodic. Chinese hamster ovary (CHO) cells transfected with the plasmid hANP-cDNA were encapsulated in biocompatible polycaprolactone capsules for intraperitoneal implantation into two-kidney, one-clip (2K1C) hypertensive rats. During a 12:12 light-dark cycle, as compared to control CHO cells, the implantation of encapsulated hANP-producing CHO cells was associated with an increase in the net excretion of water, sodium and potassium, and with a reversal of the advanced circadian phases related to renovascular hypertension in 2K1C rats. The increase in blood pressure postimplantation was delayed, and increases in renal blood flow, glomerular filtration rate, sodium output, urinary excretion and urinary cyclic GMP concentrations were also found. Implantation of encapsulated hANP-producing cells affects circadian rhythms in kidney excretion functions of 2K1C rats, and may be useful for the treatment of cardiovascular disease.
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Affiliation(s)
- L G Chen
- Department of Biomedical Engineering, School of Basic and Forensic Medicine, Sichuan University, Chengdu, PR China
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Wang T, Li H, Zhao C, Chen C, Li J, Chao J, Chao L, Xiao X, Wang DW. Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries. Gene Ther 2004; 11:1342-50. [PMID: 15175642 DOI: 10.1038/sj.gt.3302294] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Gene therapy of hypertension requires long-term expression of a therapeutic gene to achieve stable reduction of blood pressure. Human tissue kallikrein (HK) cleaves kininogen to produce a potent vasoactive peptide kinin, which plays an important role in the regulation of the cardiovascular and renal functions. In the present study, we have delivered human kallikrein cDNA with an rAAV vector to explore the potential therapeutic effects of kallikrein on hypertension and related secondary complications. A single tail vein injection of the rAAV-HK vector into the adult spontaneously hypertensive rats resulted in a significant reduction (12.0+/-2.55 mmHg, P<0.05, n=6, ANOVA) of the systolic blood pressure from 2 weeks after vector injection, when compared with the control rAAV-lacZ vector-injected rats. Weekly blood pressure monitoring showed stable hypertension-reduction effect throughout the course of the 20-week experiments. In addition, total urine microalbumin contents decreased as a result of rAAV-HK treatment. Histological analysis of various tissues showed remarkable amelioration of cardiovascular hypertrophy, renal injury and collagen depositions in the rAAV-treated group. Finally, persistent expression of the transgene product HK was confirmed by the enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. We conclude that rAAV-mediated HK delivery rendered a long-term and stable reduction of hypertension and protected against renal injury, cardiac remodeling in the spontaneously hypertensive rat model. Further studies are warranted for the development of a gene therapy strategy for human hypertension.
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Affiliation(s)
- T Wang
- Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Nandhini ATA, Thirunavukkarasu V, Anuradha CV. Potential role of kinins in the effects of taurine in high-fructose-fed rats. Can J Physiol Pharmacol 2004; 82:1-8. [PMID: 15052299 DOI: 10.1139/y03-118] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The present work investigates the involvement of kinins in the effects of taurine in fructose-fed hypertensive rats. The effects of taurine on blood pressure, plasma glucose, insulin, and the insulin sensitivity index were determined. Angiotensin-converting enzyme (ACE) activity and nitrite content in plasma, plasma and tissue kallikrein activity, and taurine content were also investigated. The blood pressure changes in response to the coadministration of inhib itors of the synthesis of nitric oxide (NO), prostaglandins (PGs), or a kinin receptor blocker along with taurine was also evaluated. Fructose-fed rats had higher blood pressure and elevated plasma levels of glucose and insulin. Kallikrein activity, taurine, and nitrite contents were significantly lower in fructose-fed rats as compared with controls. The increases in systolic blood pressure, hyperglycemia, and hyperinsulinemia were controlled by taurine administration in fructose-fed rats. ACE activity was lower, while nitrite and taurine content and kallikrein activity were higher, in taurine-supplemented rats as compared with fructose-fed rats. A significant increase in blood pressure was observed in rats cotreated with the inhibitors Hoe 140 (a kinin receptor blocker), L-NAME (a NO synthase inhibitor), or indo metha cin (a PG synthesis inhibitor) with taurine for 1 week as compared with taurine-treated fructose-fed rats. This suggests that the antihypertensive effect of taurine in fructose-fed rats was blocked by the inhibitors. Augmented kallikrein activity and, hence, increased kinin availability may be implicated in the effects of taurine in fructose-fed hypertensive rats.Key words: kallikrein, nitric oxide, angiotensin-converting enzyme, blood pressure, taurine.
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Affiliation(s)
- A T Anitha Nandhini
- Departmernt of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar 608-002, Tamil Nadu, India
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Bledsoe G, Chao L, Chao J. Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2003; 285:H1479-88. [PMID: 12816755 DOI: 10.1152/ajpheart.01129.2002] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Hypertension that results in left ventricular (LV) hypertrophy and/or fibrosis can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. To investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, an adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar-Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 wk, but had no effect from 3 to 5 wk. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV-to-heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes after kallikrein gene transfer were associated with decreases in JNK activation as well as transforming growth factor (TGF)-beta 1 and plasminogen activator inhibitor-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-beta 1, and plasminogen activator inhibitor-1 via the nitric oxide-cGMP pathway.
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Affiliation(s)
- Grant Bledsoe
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA
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Odigie IP, Ettarh RR, Adigun SA. Chronic administration of aqueous extract of Hibiscus sabdariffa attenuates hypertension and reverses cardiac hypertrophy in 2K-1C hypertensive rats. JOURNAL OF ETHNOPHARMACOLOGY 2003; 86:181-185. [PMID: 12738084 DOI: 10.1016/s0378-8741(03)00078-3] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
The effect of aqueous extract of petals of Hibiscus sabdariffa (HS) on the established stages of 2-Kidney, 1-Clip renovascular hypertension was investigated in Sprague-Dawley rats. Renovascular hypertension was induced by subjecting the animals to left renal artery clamping using a 0.2mm silver clip under ether anesthesia. Sham-operated (Sh-Op) rats served as controls. Six weeks after renal artery clamping, one group of hypertensive rats (blood pressure (BP) >140 mmHg) received HS (250 mg/kg/day) in drinking water (2K-1C+HS). The second group (2K-1C) and the sham-operated (Sh-Op) controls, received drinking water. BP was monitored weekly using rat-tail plethysmography. After 8 weeks, 2K-1C+HS had a reduction in systolic BP (139.6+/-1.6 mmHg) compared to 2K-1C (174+/-2.4 mmHg, n=5; P<0.001). No significant difference was found in BP of 2K-1C+HS and Sh-Op (139.6+/-1.6 mmHg versus 132+/-3.4 mmHg). A reduction in heart rate in 2K-1C+HS was observed (388+/-3.7 bpm versus 444+/-6.8 bpm in 2K-1C and 416+/-9.3 in Sh-Op, n=5; P<0.001). The hearts of 2K-1C were heavier than those of 2K-1C+HS (0.74+/-0.03 g versus 0.66+/-0.03 g, n=5; P<0.05). Cardiac weight of 2K-1C+HS was comparable to those of Sh-Op (0.57+/-0.04 g). Serum creatinine and plasma electrolytes were not different from controls. This study suggests that HS exhibits antihypertensive and cardioprotective effects in vivo and supports the public belief that HS may be a useful antihypertensive agent.
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Affiliation(s)
- I P Odigie
- Department of Physiology, College of Medicine of the University of Lagos, PMB 12003, Nigeria.
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Wang C, Chao J, Chao L. Adenovirus-mediated human prostasin gene delivery is linked to increased aldosterone production and hypertension in rats. Am J Physiol Regul Integr Comp Physiol 2003; 284:R1031-6. [PMID: 12626364 DOI: 10.1152/ajpregu.00660.2002] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Prostasin has been demonstrated to be an activator of epithelial sodium channels in cultured renal and bronchial epithelial cells. In this study, we evaluated the effects of adenovirus-mediated gene transfer of human prostasin on blood pressure regulation and sodium reabsorption in Wistar rats. Expression of human prostasin mRNA was identified in rat adrenal gland, liver, kidney, heart, lung, and aorta, and immunoreactive human prostasin was detected in the circulation and urine of rats receiving prostasin gene transfer. A single injection of adenovirus carrying the prostasin gene caused prolonged increases in blood pressure for 3-4 wk. Blood pressure increase was accompanied by elevated plasma aldosterone levels and reduced plasma renin activity. The increase in blood pressure and plasma aldosterone levels as well as the reduction of plasma renin activity correlated with the expression of human prostasin transgene. Elevated plasma aldosterone levels were detected at 3 days after gene transfer before the development of hypertension, indicating that stimulation of mineralocorticoid production is the primary target of prostasin. Prostasin gene transfer significantly reduced urinary K(+) excretion but increased urinary Na(+) and kallikrein excretion. Elevated renal kallikrein levels promote natriuresis, which may lead to sodium escape and prevent further increases of blood pressure after prostasin gene transfer. In summary, these results suggest that prostasin participates in blood pressure and electrolyte homeostasis by regulating the renin-angiotensin-aldosterone and kallikrein-kinin systems.
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Affiliation(s)
- Cindy Wang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425-2211, USA.
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Abstract
Chronic renal failure is one of the major health problems for the elderly. Currently, about 50% of all patients receiving chronic dialysis for end-stage renal disease (ESRD) are aged 65 years or older. Their first-year mortality rate is as high as 30%. The leading causes of ESRD in the elderly are diabetic nephropathy, hypertension and large vessel diseases, and glomerulonephritis. The elderly are also prone to developing acute renal failure induced by ischaemic injury or nephrotoxic drugs. Gene transfer in experimental animals have been tested in all of these conditions, as well as in animal kidney transplantation models, with various degrees of success. However, there are many obstacles to be overcome before gene therapy can be tested clinically for renal disorders. In particular, the major challenges include determining how to prolong and control transgene expression or antisense inhibition and how to minimise the adverse effects of viral or nonviral vectors. Once these problems are solved, gene therapy will have a role in treating age-related renal impairment.
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Affiliation(s)
- Yeong-Hau H Lien
- Department of Medicine, University of Arizona Health Sciences Center, Tucson 85724, USA.
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Francis SC, Katovich MJ, Gelband CH, Raizada MK. Gene therapy in cardiovascular disease. Current status. AMERICAN JOURNAL OF PHARMACOGENOMICS : GENOMICS-RELATED RESEARCH IN DRUG DEVELOPMENT AND CLINICAL PRACTICE 2002; 1:55-66. [PMID: 12173315 DOI: 10.2165/00129785-200101010-00007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Cardiovascular disease is the leading cause of mortality and morbidity in developed countries. Most conventional therapy is often inefficacious and tends to treat the symptoms rather than the underlying causes of the disorder. Gene therapy offers a novel approach for prevention and treatment of cardiovascular diseases. Technical advances in viral vector systems and the development of fusigenic liposome vectors have been crucial to the development of effective gene therapy strategies directed at the vasculature and myocardium in animal models. Gene transfer techniques are being evaluated as potential treatment alternatives for both genetic (familial hypercholesterolemia) and acquired occlusive vascular diseases (atherosclerosis, restenosis, arterial thrombosis) as well as for cardiac disorders including heart failure, myocardial ischemia, graft coronary arteriosclerosis and hypertension. Continued technologic advances in vector systems and promising results in human and animal gene transfer studies make the use of gene therapy a promising strategy for the treatment of cardiovascular disorders.
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Affiliation(s)
- S C Francis
- Department of Physiology, College of Medicine, University of Florida Brain Institute, Gainesville, Florida, USA
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Chao J, Wang C, Chao L. Adenovirus-mediated gene transfer for cardiovascular and renal diseases. Methods Enzymol 2002; 346:247-63. [PMID: 11883071 DOI: 10.1016/s0076-6879(02)46059-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Yu H, Song Q, Freedman BI, Chao J, Chao L, Rich SS, Bowden DW. Association of the tissue kallikrein gene promoter with ESRD and hypertension. Kidney Int 2002; 61:1030-9. [PMID: 11849458 DOI: 10.1046/j.1523-1755.2002.00198.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Kallikreins have long been implicated in human essential hypertension and associated complications. In particular, low urinary kallikrein excretion has been associated with hypertension and renal disease in African Americans. In an effort to identify the source of differential kallikrein excretion, we investigated the promoter of KLK1, the tissue kallikrein gene. The KLK1 promoter is uniquely polymorphic with a poly-G length polymorphism coupled with multiple single base substitutions. In this report, we genetically evaluated the association of KLK1 gene promoter alleles with end-stage renal disease (ESRD) in African Americans. METHODS A total of 15 haplotypes were identified in the KLK1 promoter region through detailed DNA sequence analysis. This polymorphic region was then genetically evaluated for association with ESRD in African Americans with diabetic and non-diabetic etiologies of ESRD. RESULTS The complex polymorphic nature of the promoter presents challenges to determining the alleles. We have redefined the region as six separate loci: five substitution loci and one length locus. The length locus was defined as G repeats starting at position -130 and ending at -121 on the gene. Among four relevant substitution loci for this study, one at position -131, just outside the G repeats, is an A-to-G substitution. The other three variant positions are -129, -128, and -127, all G-to-C substitutions within the G repeats. This region was genotyped in African American subjects with and without ESRD using semiautomated sequencing. Four different G repeat alleles ranging from 11.8% for 12 Gs to 52.3% for 10 Gs were observed in 86 control subjects. The C substitution of Gs ranges from 2.9% at position -127 to 8.2% at -129. When affected probands from each of 76 hypertensive ESRD families were genotyped, an association for the 12 G allele, the longest of the length locus alleles, was detected (allele specific P = 0.004 and locus total P = 0.02). When all ESRD affected individuals with hypertension from each family (107 patients in total) were used in the analysis, an even stronger association was observed for this allele (allele specific P = 0.003, locus total P = 0.01). This allele was more frequent in the hypertensive (non-diabetic) patients (0.20 in probands and 0.19 in all ESRD cases) than in the controls (0.12). No evidence of association in diabetic ESRD patients was observed (P = 0.93). CONCLUSIONS The KLK1 promoter is uniquely polymorphic. The observed genetic association suggests an etiologic effect of the KLK1 promoter on hypertension and/or hypertension associated ESRD.
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Affiliation(s)
- Hongrun Yu
- Department of Biochemistry, Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Metcalfe BL, Raizada M, Katovich MJ. Genetic targeting of the renin-angiotensin system for long-term control of hypertension. Curr Hypertens Rep 2002; 4:25-31. [PMID: 11790288 DOI: 10.1007/s11906-002-0049-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Although traditional approaches are effective for the treatment and control of hypertension, they have not succeeded in curing the disease, and have therefore reached a plateau. As a result of the completion of the Human Genome Project and the continuous advancement in gene delivery systems, it is now possible to investigate genetic means for the treatment and possible cure for hypertension. In this review we discuss the potential of genetic targeting of the renin-angiotensin system for the treatment of hypertension. We provide examples of various approaches that have used antisense technology with a high degree of success. We focus on our own research, which targets the use of antisense of the angiotensin type I receptor in various models of hypertension. Finally, we discuss the future of antisense technology in the treatment of human hypertension.
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Affiliation(s)
- Beverly L Metcalfe
- Department of Pharmacodynamics, University of Florida, College of Pharmacy, PO Box 100487, Gainesville, FL 32610-0487, USA
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Abstract
BACKGROUND Several aquaporin- (AQP) type water channels are expressed in kidney tubules and microvessels, including AQP1 in proximal tubule, thin descending limb of Henle and vasa recta, AQP2 in collecting duct apical membrane, and AQP3 and AQP4 in collecting duct basolateral membrane. Mice deficient in these aquaporins have distinct phenotypic abnormalities. AQP1 null mice are polyuria and unable to generate a concentrated urine after water deprivation. AQP2-T126M mutant mice and AQP3 null mice manifest nephrogenic diabetes insipidus (NDI) with severe polyuria, whereas AQP4 null mice have only a mild defect in maximal urinary concentrating ability. We reasoned that these mice could serve as useful models for gene replacement because of their predictable and unambiguous phenotypes. METHODS In an initial feasibility study, an adenovirus directing the expression of AQP1 was introduced into AQP1 null mice by intravenous infusion. RESULTS At 1 week after adenovirus infusion, AQP1 was seen in many proximal tubules and microvessels. Compared with untreated null mice, the treated mice were able to partially concentrate their urine and lost less weight after water deprivation. However, AQP1 transgene expression and functional correction were lost over 3-5 weeks. CONCLUSION Although there remain many technical problems to overcome, aquaporin gene replacement has potential applications in hereditary and acquired NDI, and in the transient modulation of renal fluid conservation.
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Affiliation(s)
- Alan S Verkman
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0521, USA.
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Francis SC, Raizada MK, Mangi AA, Melo LG, Dzau VJ, Vale PR, Isner JM, Losordo DW, Chao J, Katovich MJ, Berecek KH. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics 2001; 7:79-94. [PMID: 11773594 DOI: 10.1152/physiolgenomics.00073.2001] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials. Evidence for the use of gene therapy to limit neointimal hyperplasia and confer myocardial protection was presented, and it was found that augmenting local nitric oxide (NO) production using gene transfer (GT) of NO synthase or interruption of cell cycle progression through a genetic transfer of cell cycle regulatory genes limited vascular smooth muscle hyperplasia in animal models and infra-inguinal bypass patients. The results of application of vascular endothelial growth factor (VEGF) GT strategies for therapeutic angiogenesis in critical limb and myocardial ischemia in pilot clinical trials was reviewed. In addition, experimental evidence was presented that genetic manipulation of peptide systems (i.e., the renin-angiotensin II system and the kallikrein-kinin system) was effective in the treatment of systemic cardiovascular diseases such as hypertension, heart failure, and renal failure. Although, as of yet, there are no well controlled human trials proving the clinical benefits of gene therapy for cardiovascular diseases, the data presented here in animal models and in human subjects show that genetic targeting is a promising and encouraging modality, not only for the treatment and long-term control of cardiovascular diseases, but for their prevention as well.
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Affiliation(s)
- S C Francis
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida Brain Institute, Gainesville, Florida 32610, USA
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Wang C, Dobrzynski E, Chao J, Chao L. Adrenomedullin gene delivery attenuates renal damage and cardiac hypertrophy in Goldblatt hypertensive rats. Am J Physiol Renal Physiol 2001; 280:F964-71. [PMID: 11352835 DOI: 10.1152/ajprenal.2001.280.6.f964] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide that plays an important role in cardiovascular function. In this study, we employed a somatic gene delivery approach to explore its potential protective role in renovascular hypertension. A single tail vein injection of adenovirus harboring the human AM gene significantly blunted a blood pressure increase that lasted for more than 3 wk in two-kidney one-clip (2K1C) hypertensive rats. The expression of human AM mRNA was detected in the kidney, adrenal gland, heart, lung, and liver, and immunoreactive human AM was detected in the plasma and urine of 2K1C rats after human AM gene delivery. A maximal blood pressure difference of 28 mmHg was observed 10 days after AM gene delivery, compared with that in rats injected with the control virus carrying the LacZ gene. Human AM gene delivery significantly attenuated increases in the ratio of left ventricular weight to heart weight, cardiomyocyte diameter, and fibrosis in the heart, as well as glomerular sclerosis, tubular injuries, and protein casts in the kidney. The beneficial effects of AM gene delivery were accompanied by increased urinary cAMP levels, indicating activation of AM receptors. These findings provide new insights into the role of AM in renovascular hypertension and may have significance in therapeutic applications in cardiovascular diseases.
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Affiliation(s)
- C Wang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Abstract
BACKGROUND Renal kallikrein has been linked with inheritance of arterial hypertension and with sensitivity to drug nephrotoxicity. Identification of a cause--effect relationship between low kallikrein and intermediate phenotypes has been hampered by the lack of adequate animal models. METHODS Kallikrein was measured in tissues obtained from rats inbred for low urinary kallikrein excretion (LKR) and wild-type controls. Blood pressure and indices of myocardial contractility were recorded via an intraventricular cannula connected to a transducer. The functional relevance of endogenous angiotensin II (Ang II) in LKR was explored by determining the effect of Ang II subtype 1 (AT(1)) receptor blockade on glomerular filtration rate, renal blood flow, and urinary sodium excretion. In addition, sensitivity to gentamycin-induced nephrotoxicity was evaluated. RESULTS Kallikrein activity was reduced by 60% in the kidney of LKR (P < 0.01), whereas it was increased in the heart (P < 0.05) and was unaltered in the pancreas, liver, and salivary glands. Heart rate and myocardial contractility were reduced, and the mean blood pressure (MBP) was increased in LKR as compared with controls (P < 0.05). LKR exhibited polydipsia, polyuria, glomerular hyperfiltration, and reduced fractional sodium excretion under basal conditions and impaired renal vasodilation in response to volume expansion. These functional alterations were significantly attenuated by AT(1) receptor blockade. Gentamycin reduced the glomerular filtration rate in LKR, but not in controls. CONCLUSIONS In LKR, unopposed activity of Ang II appears to be responsible for increased glomerular hydrostatic pressure and augmented tubular reabsorption. Balance between the kallikrein-kinin and renin-angiotensin systems is essential for normal renal function.
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Affiliation(s)
- P Madeddu
- National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy.
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Silva JA, Araujo RC, Baltatu O, Oliveira SM, Tschöpe C, Fink E, Hoffmann S, Plehm R, Chai KX, Chao L, Chao J, Ganten D, Pesquero JB, Bader M. Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J 2000; 14:1858-60. [PMID: 11023967 DOI: 10.1096/fj.99-1010fje] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
To evaluate the cardiovascular actions of kinins, we established a transgenic rat line harboring the human tissue kallikrein gene, TGR(hKLK1). Under the control of the zinc-inducible metallothionein promoter, the transgene was expressed in most tissues including the heart, kidney, lung, and brain, and human kallikrein was detected in the urine of transgenic animals. Transgenic rats had a lower 24-h mean arterial pressure in comparison with control rats, which was further decreased when their diet was supplemented with zinc. The day/night rhythm of blood pressure was significantly diminished in TGR(hKLK1) animals, whereas the circadian rhythms of heart rate and locomotor activity were unaffected. Induction of cardiac hypertrophy by isoproterenol treatment revealed a marked protective effect of the kallikrein transgene because the cardiac weight of TGR(hKLK1) increased significantly less, and the expression of atrial natriuretic peptide and collagen III as markers for hypertrophy and fibrosis, respectively, were less enhanced. The specific kinin-B2 receptor antagonist, icatibant, abolished this cardioprotective effect. In conclusion, the kallikrein-kinin system is an important determinant in the regulation of blood pressure and its circadian rhythmicity. It also exerts antihypertrophic and antifibrotic actions in the heart.
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Affiliation(s)
- J A Silva
- Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany
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Zhang JJ, Yoshida H, Chao L, Chao J. Human adrenomedullin gene delivery protects against cardiac hypertrophy, fibrosis, and renal damage in hypertensive dahl salt-sensitive rats. Hum Gene Ther 2000; 11:1817-27. [PMID: 10986555 DOI: 10.1089/10430340050129440] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Abstract
Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiac and renal functions. Our previous study showed that delivery of the human AM gene in the form of naked DNA caused a prolonged reduction of blood pressure in genetically hypertensive rats. In this study, we evaluated potential protective effects of adenovirus-mediated AM gene delivery on salt-induced cardiorenal lesions in hypertensive Dahl saltsensitive (DSS) rats. Adenovirus carrying the human AM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM) was generated by homologous recombination of E. coli. Expression of recombinant human AM was detected by a radioimmunoassay in the medium of human embryonic kidney 293 cells transfected with Ad.CMV-hAM. A single intravenous injection of Ad.CMV-hAM caused a significant reduction of systolic blood pressure for 4 weeks in DSS rats compared with control rats with or without injection of adenovirus carrying the green fluorescent protein gene. AM gene delivery significantly reduced left ventricular mass and urinary protein, increased cAMP levels, and enhanced renal function as evidenced by increases in glomerular filtration rate and renal blood flow. Morphological investigations showed that AM gene transfer reduced cardiomyocyte diameter and interstitial fibrosis in the heart as well as glomerular sclerosis, tubular disruption, and protein cast accumulation in the kidney. Expression of human AM mRNA was identified in rat heart, kidney, lung, liver, and aorta, and immunoreactive human AM levels were measured in rat plasma and urine. These results indicate that human AM gene delivery protects against salt-induced hypertension and cardiac and renal lesions in DSS rats via activation of cAMP as a second messenger. These findings provide new insights into the role of AM in salt-induced hypertension and may have implications in therapeutic applications to salt-related cardiovascular and renal diseases.
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Affiliation(s)
- J J Zhang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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Wolf WC, Yoshida H, Agata J, Chao L, Chao J. Human tissue kallikrein gene delivery attenuates hypertension, renal injury, and cardiac remodeling in chronic renal failure. Kidney Int 2000; 58:730-9. [PMID: 10916096 DOI: 10.1046/j.1523-1755.2000.00219.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Tissue kallikrein cleaves kininogen substrate to produce the potent vasodilating peptide kinin, which plays important roles in cardiovascular and renal function. To explore cardiac and renal potential protective effects of kallikrein gene delivery in chronic renal failure, we delivered adenovirus carrying the human tissue kallikrein cDNA (cHK) into rats with 5/6 reduction of renal mass. METHODS Expression of human tissue kallikrein in rats was assessed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting. Physiological parameters monitored in rats included systolic blood pressure, heart rate, and urinary excretion of protein, albumin, kinin, cGMP, cAMP, and nitrate/nitrites. Systemic and regional hemodynamics were measured by fluorescent-labeled microspheres. Heart weight and myocyte diameter were used to assess left ventricular hypertrophy. Quantitative and qualitative morphological analyses were used to evaluate histologic changes in kidney and heart sections. RESULTS Active tissue kallikrein reached a peak serum level of 463 +/- 76 ng/mL following gene delivery and returned to control levels within 21 days. A maximal blood pressure reduction of 37 mm Hg was observed within one week in rats receiving kallikrein gene delivery as compared with control rats receiving adenovirus containing the luciferase gene (159 +/- 5 vs. 196 +/- 6 mm Hg, N = 15, P < 0.001), and a significant blood pressure difference continued for five weeks postgene delivery. Kallikrein gene delivery significantly decreased total urinary protein and albumin excretion and increased levels of urinary kinin, nitrite/nitrate, and cGMP levels. Cardiac output and regional blood flow were also increased, while peripheral vascular resistance decreased. Kallikrein gene transfer reduced glomerular sclerotic lesions, tubular damage, lumenal protein cast accumulation, and interstitial inflammation in the kidney. Myocardial hypertrophy and fibrosis were also attenuated in rats receiving kallikrein gene delivery. CONCLUSIONS These findings indicated that kallikrein gene delivery attenuates hypertension and protects against renal injury and cardiac remodeling in the rat remnant kidney model of chronic renal failure.
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Affiliation(s)
- W C Wolf
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA
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Wang D, Yoshida H, Song Q, Chao L, Chao J. Enhanced renal function in bradykinin B(2) receptor transgenic mice. Am J Physiol Renal Physiol 2000; 278:F484-91. [PMID: 10710553 DOI: 10.1152/ajprenal.2000.278.3.f484] [Citation(s) in RCA: 25] [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
The tissue kallikrein-kinin system has been recognized as a paracrine and/or autocrine hormonal system that regulates arterial pressure, renal hemodynamics, and electrolyte excretion. We have created a transgenic mouse model overexpressing human bradykinin B(2) receptor, and the mice developed lifetime hypotension. With this animal model, we further analyzed the potential role of B(2) receptors in regulation of renal function. Baseline urinary excretion, urinary potassium excretion, and pH were significantly increased in transgenic mice, whereas urinary sodium excretion and serum sodium concentration were unaltered. Transgenic mice exhibited increased renal blood flow, glomerular filtration rate, and urine flow. Enhanced renal function was accompanied by significant increases in urinary nitrate/nitrite, cGMP, and cAMP levels with unaltered urinary kinin levels in transgenic mice compared with control siblings. Renal cGMP and cAMP content was also significantly increased in transgenic mice. Because the renin-angiotensin system exerts vasoconstriction buffering vasodilation of the kallikrein-kinin system, expression of renin-angiotensin components was examined by Northern blot analysis. We found a significant increase in hepatic angiotensinogen expression with no changes in renal renin and pulmonary angiotensin-converting enzyme mRNA levels in B(2) receptor transgenic mice. These studies showed that overexpression of B(2) receptors in transgenic mice resulted in hypotension and enhanced renal function through activation of nitric oxide-cGMP and cAMP signal transduction pathways.
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Affiliation(s)
- D Wang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Yang B, Ma T, Dong JY, Verkman AS. Partial correction of the urinary concentrating defect in aquaporin-1 null mice by adenovirus-mediated gene delivery. Hum Gene Ther 2000; 11:567-75. [PMID: 10724035 DOI: 10.1089/10430340050015752] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The feasibility of water channel gene delivery to kidney tubules and microvessels was evaluated by delivery of an adenovirus encoding aquaporin 1 (AQP1-Ad5) to transgenic AQP1 null mice. In wild-type mice, AQP1 is expressed in kidney proximal tubule, thin descending limb of Henle, and descending vasa recta, where urine osmolality (Uosm) increases from 1000-1500 mOsm (before) to 2500-3500 mOsm after 36 hr of water deprivation. Uosm in AQP1 null mice remains nearly fixed at 650-750 mOsm. AQP1-Ad5 (with a CMV promoter) was generated and purified. Infection of CHO cells gave strong uniform AQP1 expression with plasma membrane localization and eightfold increased water permeability over noninfected cells. AQP1-Ad5 was delivered to 20 to 25-g AQP1 null mice by tail vein infusion (0-10(10) PFU). At 3-7 days, AQP1 protein expression was strongest in liver (approximately 20 microg of AQP1 protein per liver) and next strongest in kidney, with expression in proximal tubule apical and basolateral membranes, and renal microvessels. Functional analysis showed increased water permeability in apical membrane vesicles from proximal tubule. AQP1 expression was not detected in glomerulus, limb of Henle, or collecting duct. In water-deprived null mice receiving 5 x 10(9) PFU of AQP1-Ad5, Uosm increased by up to 510 mOsm (mean increase, 225 +/- 24 mOsm; n = 33 mice). Whereas the control null mice became lethargic and lost 34.2 +/- 0.6% body weight, the virus-treated mice remained relatively active and lost 32.3 +/- 0.7% body weight. Viral DNA and AQP1 transcript were detected in kidney and liver of null mice up to 17 weeks after virus infusion; partial correction of the urinary concentrating defect persisted for 3-5 weeks. These results demonstrate partial functional correction of a urinary concentrating defect by adenoviral delivery of the AQP1 gene.
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Affiliation(s)
- B Yang
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, USA
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Madeddu P, Salis MB, Emanueli C. Altered baroreflex control of heart rate in bradykinin B2-receptor knockout mice. IMMUNOPHARMACOLOGY 1999; 45:21-7. [PMID: 10614985 DOI: 10.1016/s0162-3109(99)00053-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Recently, we have shown that a knockout mouse strain lacking the bradykinin B2-receptor gene exhibits an accelerated heart rate (HR) under basal conditions, this alteration being associated with mildly elevated blood pressure (BP) levels and ultimately with the development of cardiomyopathy. The goal of the present study was to determine whether genetic disruption of the B2-receptor alters autonomic cardiovascular reflexes to acute or chronic changes in BP. The direct mean BP and HR levels of unrestrained B2 knockout mice (B2-/-) were higher than those of wild type (B2+/+) controls (131 +/- 2 vs. 105 +/- 2 mm Hg and 480 +/- 5 vs. 414 +/- 8 beats/min, P < 0.01 for both comparisons). The difference in HR observed between groups under basal conditions was nullified by the acute administration of propranolol and atropine as well as by hexamethonium; it was attenuated by long-term blockade of angiotensin AT1 receptors. In B2-/- mice, the presence of an alteration in baroreceptor regulation of HR was supported by a reduced gain in the HR responses to acute nitroprusside-induced hypotension or phenylephrine-induced hypertension (slope of the regression line: 0.82 +/- 0.07 vs. 5.58 +/- 0.08 beats/min per mmHg in B2+/+, P < 0.01), as well as by an exaggerated tachycardic response to chronic hypertension induced by clipping of the left renal artery (60 +/- 3 vs. 15 +/- 3 beats/min in B2+/+, P < 0.01). Our findings indicate that disruption of the bradykinin B2-receptor gene is associated with an impaired baroreflex control of HR. The combination of chronically elevated resting HR and impaired baroreflex control could contribute to the development of cardiomyopathy in these animals.
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Affiliation(s)
- P Madeddu
- National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy
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Murakami H, Miao RQ, Chao L, Chao J. Adenovirus-mediated kallikrein gene transfer inhibits neointima formation via increased production of nitric oxide in rat artery. IMMUNOPHARMACOLOGY 1999; 44:137-43. [PMID: 10604537 DOI: 10.1016/s0162-3109(99)00120-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Tissue kallikrein cleaves kininogen substrate to produce vasoactive kinin peptides that have been implicated to play a role in the proliferation of vascular smooth muscle cells (VSMC). In order to explore potential roles of the kallikrein-kinin system in vascular biology, we evaluated the effects of adenovirus-mediated kallikrein gene delivery on neointima formation in balloon-injured rat artery. Infection of isolated rat aortic segments with adenovirus containing the human tissue kallikrein gene resulted in a time-dependent secretion of recombinant human tissue kallikrein, and significant increases in nitric oxide (NOx) and guanosine 3',5'-cyclic monophosphate (cGMP) levels post gene transfer. Human tissue kallikrein gene was delivered locally via adenoviral vectors into left common carotid artery after balloon angioplasty. Two weeks following gene transfer, we observed a 39% reduction in intima/media ratio at the injured vessel as compared to that of rats receiving control virus (n = 8, P < .01). Delivery of N(omega)-nitro-L-arginine methyl ester (L-NAME), a NOx synthase inhibitor via minipump for 2 weeks, blocked the protective effect and reversed the intima/media ratio to that of control rats (n = 5, P < .01). These results indicated that human tissue kallikrein gene delivery inhibits neointima formation via NO-cGMP signaling pathway. This study provides new insights into the role of the vascular kallikrein-kinin system and may have significant implications for gene therapy in treating occlusive vascular diseases.
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Affiliation(s)
- H Murakami
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA
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Dobrzynski E, Yoshida H, Chao J, Chao L. Adenovirus-mediated kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxycorticosterone-salt rats. IMMUNOPHARMACOLOGY 1999; 44:57-65. [PMID: 10604525 DOI: 10.1016/s0162-3109(99)00121-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
To demonstrate potential therapeutic effects of kallikrein gene delivery in salt-induced hypertension and renal diseases, we delivered adenovirus carrying the human tissue kallikrein gene (Ad.CMV-cHK) into deoxycorticosterone acetate (DOCA)-salt hypertensive rats. A single intravenous injection of Ad.CMV-cHK caused a delay in the rise of blood pressure that began 2 days post gene delivery and lasted for more than 23 days. A maximal blood pressure reduction of 50 mm Hg was observed in rats receiving kallikrein gene delivery, as compared to rats receiving adenovirus containing the luciferase gene (Ad.CMV-Luc) (172 +/- 5 vs. 222 +/- 13 mm Hg, n = 6, P < 0.01). Throughout the experimental period, a blood pressure reduction of at least 32 mm Hg was observed in the DOCA-salt rats injected with Ad.CMV-cHK as compared to DOCA-salt rats receiving control adenovirus. Immunoreactive human tissue kallikrein levels were detected in rat serum and urine post gene delivery. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in urinary excretion, urinary protein levels and body weight. Morphological examination of the kidney showed that kallikrein gene transfer significantly reduced DOCA-salt-induced glomerular sclerotic lesions, brush border disruption of proximal tubules, tubular dilatation and protein cast accumulation. These findings showed that the expression of human tissue kallikrein via gene delivery has protective effects against hypertension and renal injury in DOCA-salt hypertensive rats.
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Affiliation(s)
- E Dobrzynski
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA
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