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Moore SC, Vaz de Castro PAS, Yaqub D, Jose PA, Armando I. Anti-Inflammatory Effects of Peripheral Dopamine. Int J Mol Sci 2023; 24:13816. [PMID: 37762126 PMCID: PMC10530375 DOI: 10.3390/ijms241813816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 08/18/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Dopamine is synthesized in the nervous system where it acts as a neurotransmitter. Dopamine is also synthesized in a number of peripheral organs as well as in several types of cells and has organ-specific functions and, as demonstrated more recently, is involved in the regulation of the immune response and inflammatory reaction. In particular, the renal dopaminergic system is very important in the regulation of sodium transport and blood pressure and is particularly sensitive to stimuli that cause oxidative stress and inflammation. This review is focused on how dopamine is synthesized in organs and tissues and the mechanisms by which dopamine and its receptors exert their effects on the inflammatory response.
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Affiliation(s)
| | | | | | | | - Ines Armando
- Division of Kidney Diseases and Hypertension, Department of Medicine, The George Washington School of Medicine and Health Sciences, Washington, DC 20037, USA; (S.C.M.); (P.A.S.V.d.C.); (D.Y.); (P.A.J.)
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2
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Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
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Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
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3
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Interactions between the intrarenal dopaminergic and the renin-angiotensin systems in the control of systemic arterial pressure. Clin Sci (Lond) 2022; 136:1205-1227. [PMID: 35979889 DOI: 10.1042/cs20220338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022]
Abstract
Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension.
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Leisman G, Sheldon D. Tics and Emotions. Brain Sci 2022; 12:brainsci12020242. [PMID: 35204005 PMCID: PMC8870550 DOI: 10.3390/brainsci12020242] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/06/2022] [Accepted: 02/07/2022] [Indexed: 02/04/2023] Open
Abstract
Tics can be associated with neurological disorders and are thought to be the result of dysfunctional basal ganglia pathways. In Tourette Syndrome (TS), excess dopamine in the striatum is thought to excite the thalamo-cortical circuits, producing tics. When external stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, more dopamine is produced, furthering the excitation of tic-producing pathways. Emotional processing structures in the limbic are also activated during tics, providing further evidence of a possible emotional component in motor ticking behaviors. The purpose of this review is to better understand the relationship between emotional states and ticking behavior. We found support for the notion that premonitory sensory phenomena (PSP), sensory stimulation, and other environmental stressors that impact the HPA axis can influence tics through dopaminergic neurotransmission. Dopamine plays a vital role in cognition and motor control and is an important neurotransmitter in the pathophysiology of other disorders such as obsessive–compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), which tend to be comorbid with ticking disorders and are thought to use similar pathways. It is concluded that there is an emotional component to ticking behaviors. Emotions primarily involving anxiety, tension, stress, and frustration have been associated with exacerbated tics, with PSP contributing to these feelings.
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Affiliation(s)
- Gerry Leisman
- Movement and Cognition Laboratory, Department of Physical Therapy, University of Haifa, Haifa 3498838, Israel
- Department of Clinical Neurophysiology, Institute for Neurology and Neurosurgery, Universidad de la Ciencias Médicas, Havana 10400, Cuba
- Correspondence:
| | - Dana Sheldon
- Department of Cognitive Neuroscience, George Washington University, Washington, DC 20052, USA;
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Brown LE, Reyes G, Albrecht EA. Crotalus atrox venom-induced cellular toxicity: Early wound progression involves reactive oxygen species. J Appl Toxicol 2021; 42:852-863. [PMID: 34725845 DOI: 10.1002/jat.4262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/15/2021] [Accepted: 10/15/2021] [Indexed: 11/06/2022]
Abstract
Understanding the mechanisms that produce cellular cytotoxicity is fundamental in the field of toxicology. Cytotoxic stimuli can include organic toxins such as hemorrhagic snake venom, which can lead to secondary complications such as the development of necrotic tissue and profuse scarring. These clinical manifestations mimic cytotoxic responses induce by other organic compounds such as organic acids. We used hemorrhagic snake venom and human embryonic kidney cells (HEK 293T) as a model system to better understand the cellular responses involved in venom induced cytotoxicity. Cells stimulated with Crotalus atrox (CA) (western diamondback) venom for 4 or 10 h demonstrated significant cytotoxicity. Results from 2',7'-Dichlorodihydrofluorescein diacetate (H2 DCF-DA) assays determine CA venom stimulation induces a robust production of reactive oxygen species (ROS) over a 3-h time course. In contrast, pretreatment with polyethylene glycol (PEG)-catalase or N-acetyl cysteine (NAC) prior to CA venom stimulation significantly blunted H2 DCFDA fluorescence fold changes and showed greater cytoprotective effects than cells stimulated with CA venom alone. Pre- incubating HEK293T cells with the NADPH oxidase (NOX) pan-inhibitor VAS2870 prior venom stimulation significantly minimized the venom-induced oxidative burst at early timepoints (≤2 h). Collectively, our experiments show that pre-application of antioxidants reduces CA venom induce cellular toxicity. This result highlights the importance of ROS in the early stages of cytotoxicity and suggests muting ROS production in noxious injuries may increase positive clinical outcomes.
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Affiliation(s)
- Lindsay E Brown
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia, USA
| | - Giovanni Reyes
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia, USA
| | - Eric A Albrecht
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia, USA
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Lee H, Jiang X, Perwaiz I, Yu P, Wang J, Wang Y, Hüttemann M, Felder RA, Sibley DR, Polster BM, Rozyyev S, Armando I, Yang Z, Qu P, Jose PA. Dopamine D 5 receptor-mediated decreases in mitochondrial reactive oxygen species production are cAMP and autophagy dependent. Hypertens Res 2021; 44:628-641. [PMID: 33820956 PMCID: PMC8369611 DOI: 10.1038/s41440-021-00646-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 11/10/2019] [Accepted: 12/03/2019] [Indexed: 01/31/2023]
Abstract
Overproduction of reactive oxygen species (ROS) plays an important role in the pathogenesis of hypertension. The dopamine D5 receptor (D5R) is known to decrease ROS production, but the mechanism is not completely understood. In HEK293 cells overexpressing D5R, fenoldopam, an agonist of the two D1-like receptors, D1R and D5R, decreased the production of mitochondria-derived ROS (mito-ROS). The fenoldopam-mediated decrease in mito-ROS production was mimicked by Sp-cAMPS but blocked by Rp-cAMPS. In human renal proximal tubule cells with DRD1 gene silencing to eliminate the confounding effect of D1R, fenoldopam still decreased mito-ROS production. By contrast, Sch23390, a D1R and D5R antagonist, increased mito-ROS production in the absence of D1R, D5R is constitutively active. The fenoldopam-mediated inhibition of mito-ROS production may have been related to autophagy because fenoldopam increased the expression of the autophagy hallmark proteins, autophagy protein 5 (ATG5), and the microtubule-associated protein 1 light chain (LC)3-II. In the presence of chloroquine or spautin-1, inhibitors of autophagy, fenoldopam further increased ATG5 and LC3-II expression, indicating an important role of D5R in the positive regulation of autophagy. However, when autophagy was inhibited, fenoldopam was unable to inhibit ROS production. Indeed, the levels of these autophagy hallmark proteins were decreased in the kidney cortices of Drd5-/- mice. Moreover, ROS production was increased in mitochondria isolated from the kidney cortices of Drd5-/- mice, relative to Drd5+/+ littermates. In conclusion, D5R-mediated activation of autophagy plays a role in the D5R-mediated inhibition of mito-ROS production in the kidneys.
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Affiliation(s)
- Hewang Lee
- Department of Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC, USA,Institute of Heart and Vessel Diseases, Affiliated Second Hospital, Dalian Medical University, Dalian, China,Division of Nephrology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA,Center for Molecular Physiology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC, USA,Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA,Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Xiaoliang Jiang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Imran Perwaiz
- Institute of Heart and Vessel Diseases, Affiliated Second Hospital, Dalian Medical University, Dalian, China
| | - Peiying Yu
- Division of Nephrology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA,Center for Molecular Physiology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC, USA,Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA
| | - Jin Wang
- Institute of Heart and Vessel Diseases, Affiliated Second Hospital, Dalian Medical University, Dalian, China
| | - Ying Wang
- Institute of Heart and Vessel Diseases, Affiliated Second Hospital, Dalian Medical University, Dalian, China
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics and Cardiovascular Research Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Robin A. Felder
- Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - David R. Sibley
- Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
| | - Brian M. Polster
- Department of Anesthesiology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Selim Rozyyev
- Department of Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC, USA
| | - Ines Armando
- Department of Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC, USA,Division of Nephrology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA,Center for Molecular Physiology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC, USA,Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA
| | - Zhiwei Yang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Peng Qu
- Institute of Heart and Vessel Diseases, Affiliated Second Hospital, Dalian Medical University, Dalian, China
| | - Pedro A. Jose
- Department of Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC, USA,Division of Nephrology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA,Center for Molecular Physiology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC, USA,Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA,Department of Pharmacology and Physiology, School of Medicine & Health Sciences, George Washington University, Washington, DC, USA
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Yang J, Villar VAM, Jose PA, Zeng C. Renal Dopamine Receptors and Oxidative Stress: Role in Hypertension. Antioxid Redox Signal 2021; 34:716-735. [PMID: 32349533 PMCID: PMC7910420 DOI: 10.1089/ars.2020.8106] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: The kidney plays an important role in the long-term control of blood pressure. Oxidative stress is one of the fundamental mechanisms responsible for the development of hypertension. Dopamine, via five subtypes of receptors, plays an important role in the control of blood pressure by various mechanisms, including the inhibition of oxidative stress. Recent Advances: Dopamine receptors exert their regulatory function to decrease the oxidative stress in the kidney and ultimately maintain normal sodium balance and blood pressure homeostasis. An aberration of this regulation may be involved in the pathogenesis of hypertension. Critical Issues: Our present article reviews the important role of oxidative stress and intrarenal dopaminergic system in the regulation of blood pressure, summarizes the current knowledge on renal dopamine receptor-mediated antioxidation, including decreasing reactive oxygen species production, inhibiting pro-oxidant enzyme nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and stimulating antioxidative enzymes, and also discusses its underlying mechanisms, including the increased activity of G protein-coupled receptor kinase 4 (GRK4) and abnormal trafficking of renal dopamine receptors in hypertensive status. Future Directions: Identifying the mechanisms of renal dopamine receptors in the regulation of oxidative stress and their contribution to the pathogenesis of hypertension remains an important research focus. Increased understanding of the role of reciprocal regulation between renal dopamine receptors and oxidative stress in the regulation of blood pressure may give us novel insights into the pathogenesis of hypertension and provide a new treatment strategy for hypertension.
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Affiliation(s)
- Jian Yang
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Van Anthony M Villar
- Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Pedro A Jose
- Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Chunyu Zeng
- Department of Cardiology, Fujian Heart Medical Center, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China.,Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China
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8
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Jiang X, Shao M, Liu X, Liu X, Zhang X, Wang Y, Yin K, Wang S, Hu Y, Jose PA, Zhou Z, Xu F, Yang Z. Reversible Treatment of Pressure Overload-Induced Left Ventricular Hypertrophy through Drd5 Nucleic Acid Delivery Mediated by Functional Polyaminoglycoside. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003706. [PMID: 33717857 PMCID: PMC7927605 DOI: 10.1002/advs.202003706] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/23/2020] [Indexed: 05/12/2023]
Abstract
Left ventricular hypertrophy and fibrosis are major risk factors for heart failure, which require timely and effective treatment. Genetic therapy has been shown to ameliorate hypertrophic cardiac damage. In this study, it is found that in mice, the dopamine D5 receptor (D5R) expression in the left ventricle (LV) progressively decreases with worsening of transverse aortic constriction-induced left ventricular hypertrophy. Then, a reversible treatment of left ventricular hypertrophy with Drd5 nucleic acids delivered by tobramycin-based hyperbranched polyaminoglycoside (SS-HPT) is studied. The heart-specific increase in D5R expression by SS-HPT/Drd5 plasmid in the early stage of left ventricular hypertrophy attenuates cardiac hypertrophy and fibrosis by preventing oxidative and endoplasmic reticulum (ER) stress and ameliorating autophagic dysregulation. By contrast, SS-HPT/Drd5 siRNA promotes the progression of left ventricular hypertrophy and accelerates the deterioration of myocardial function into heart failure. The reduction in cardiac D5R expression and dysregulated autophagy are observed in patients with hypertrophic cardiomyopathy and heart failure. The data show a cardiac-specific beneficial effect of SS-HPT/Drd5 plasmid on myocardial remodeling and dysfunction, which may provide an effective therapy of patients with left ventricular hypertrophy and heart failure.
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Affiliation(s)
- Xiaoliang Jiang
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS & PUMC), and Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases5 Pan Jia Yuan Nan Li, Chaoyang DistrictBeijing100021P. R. China
| | - Meiyu Shao
- Key Lab of Biomedical Materials of Natural MacromoleculesMinistry of EducationBeijing Laboratory of Biomedical MaterialsBeijing Advanced Innovation Center for Soft Matter Science and EngineeringBeijing University of Chemical TechnologyBeijing100029P. R. China
| | - Xue Liu
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS & PUMC), and Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases5 Pan Jia Yuan Nan Li, Chaoyang DistrictBeijing100021P. R. China
| | - Xing Liu
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS & PUMC), and Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases5 Pan Jia Yuan Nan Li, Chaoyang DistrictBeijing100021P. R. China
| | - Xu Zhang
- Department of Hepato‐Biliary‐Pancreatic SurgeryHenan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityZhengzhouHenan450003P. R. China
| | - Yuming Wang
- Department of Hepato‐Biliary‐Pancreatic SurgeryHenan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityZhengzhouHenan450003P. R. China
| | - Kunlun Yin
- State Key Laboratory of Cardiovascular DiseaseBeijing Key Laboratory for Molecular Diagnostics of Cardiovascular DiseasesDiagnostic Laboratory ServiceFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100037P. R. China
| | - Shuiyun Wang
- Department of Cardiovascular SurgeryState Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100037P. R. China
| | - Yang Hu
- Key Lab of Biomedical Materials of Natural MacromoleculesMinistry of EducationBeijing Laboratory of Biomedical MaterialsBeijing Advanced Innovation Center for Soft Matter Science and EngineeringBeijing University of Chemical TechnologyBeijing100029P. R. China
| | - Pedro A Jose
- Department of Pharmacology and PhysiologyThe George Washington University School of Medicine & Health SciencesWashingtonDC20052USA
- Department of MedicineDivision of Kidney Diseases & HypertensionThe George Washington University School of Medicine & Health SciencesWashingtonDC20052USA
| | - Zhou Zhou
- State Key Laboratory of Cardiovascular DiseaseBeijing Key Laboratory for Molecular Diagnostics of Cardiovascular DiseasesDiagnostic Laboratory ServiceFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100037P. R. China
| | - Fu‐Jian Xu
- Key Lab of Biomedical Materials of Natural MacromoleculesMinistry of EducationBeijing Laboratory of Biomedical MaterialsBeijing Advanced Innovation Center for Soft Matter Science and EngineeringBeijing University of Chemical TechnologyBeijing100029P. R. China
| | - Zhiwei Yang
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS & PUMC), and Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases5 Pan Jia Yuan Nan Li, Chaoyang DistrictBeijing100021P. R. China
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Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications. Biomolecules 2021; 11:biom11020254. [PMID: 33578816 PMCID: PMC7916607 DOI: 10.3390/biom11020254] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 12/21/2022] Open
Abstract
The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1-D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.
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The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension. Biomedicines 2021; 9:biomedicines9020139. [PMID: 33535566 PMCID: PMC7912729 DOI: 10.3390/biomedicines9020139] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 01/11/2023] Open
Abstract
The kidney is critical in the long-term regulation of blood pressure. Oxidative stress is one of the many factors that is accountable for the development of hypertension. The five dopamine receptor subtypes (D1R–D5R) have important roles in the regulation of blood pressure through several mechanisms, such as inhibition of oxidative stress. Dopamine receptors, including those expressed in the kidney, reduce oxidative stress by inhibiting the expression or action of receptors that increase oxidative stress. In addition, dopamine receptors stimulate the expression or action of receptors that decrease oxidative stress. This article examines the importance and relationship between the renal dopaminergic system and oxidative stress in the regulation of renal sodium handling and blood pressure. It discusses the current information on renal dopamine receptor-mediated antioxidative network, which includes the production of reactive oxygen species and abnormalities of renal dopamine receptors. Recognizing the mechanisms by which renal dopamine receptors regulate oxidative stress and their degree of influence on the pathogenesis of hypertension would further advance the understanding of the pathophysiology of hypertension.
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11
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De Miguel C, Hamrick WC, Sedaka R, Jagarlamudi S, Asico LD, Jose PA, Cuevas S. Uncoupling Protein 2 Increases Blood Pressure in DJ -1 Knockout Mice. J Am Heart Assoc 2020; 8:e011856. [PMID: 30995881 PMCID: PMC6512091 DOI: 10.1161/jaha.118.011856] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background The redox-sensitive chaperone DJ -1 and uncoupling protein 2 are protective against mitochondrial oxidative stress. We previously reported that renal-selective depletion and germline deletion of DJ -1 increases blood pressure in mice. This study aimed to determine the mechanisms involved in the oxidative stress-mediated hypertension in DJ -1 -/- mice. Methods and Results There were no differences in sodium excretion, renal renin expression, renal NADPH oxidase activity, and serum creatinine levels between DJ -1 -/- and wild-type mice. Renal expression of nitro-tyrosine, malondialdehyde, and urinary kidney injury marker-1 were increased in DJ -1 -/- mice relative to wild-type littermates. mRNA expression of mitochondrial heat shock protein 60 was also elevated in kidneys from DJ -1 -/- mice, indicating the presence of oxidative stress. Tempol-treated DJ -1 -/- mice presented higher serum nitrite/nitrate levels than vehicle-treated DJ -1 -/- mice, suggesting a role of the NO system in the high blood pressure of this model. Tempol treatment normalized renal kidney injury marker-1 and malondialdehyde expression as well as blood pressure in DJ -1 -/- mice, but had no effect in wild-type mice. The renal Ucp2 mRNA expression was increased in DJ -1 -/- mice versus wild-type and was also normalized by tempol. The renal-selective silencing of Ucp2 led to normalization of blood pressure and serum nitrite/nitrate ratio in DJ -1 -/- mice. Conclusions The deletion of DJ -1 leads to oxidative stress-induced hypertension associated with downregulation of NO function, and overexpression of Ucp2 in the kidney increases blood pressure in DJ -1 -/- mice. To our knowledge, this is the first report providing evidence of the role of uncoupling protein 2 in blood pressure regulation.
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Affiliation(s)
- Carmen De Miguel
- 1 Section of Cardio-Renal Physiology and Medicine Division of Nephrology Department of Medicine University of Alabama at Birmingham AL
| | - William C Hamrick
- 1 Section of Cardio-Renal Physiology and Medicine Division of Nephrology Department of Medicine University of Alabama at Birmingham AL
| | - Randee Sedaka
- 1 Section of Cardio-Renal Physiology and Medicine Division of Nephrology Department of Medicine University of Alabama at Birmingham AL
| | - Sudha Jagarlamudi
- 2 Division of Renal Diseases & Hypertension Department of Medicine The George Washington University School of Medicine and Health Sciences Washington DC
| | - Laureano D Asico
- 2 Division of Renal Diseases & Hypertension Department of Medicine The George Washington University School of Medicine and Health Sciences Washington DC
| | - Pedro A Jose
- 2 Division of Renal Diseases & Hypertension Department of Medicine The George Washington University School of Medicine and Health Sciences Washington DC
| | - Santiago Cuevas
- 3 Research Center for Genetic Medicine Children's National Health System Washington DC
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12
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Yang J, Asico LD, Beitelshees AL, Feranil JB, Wang X, Jones JE, Armando I, Cuevas SG, Schwartz GL, Gums JG, Chapman AB, Turner ST, Boerwinkle E, Cooper-DeHoff RM, Johnson JA, Felder RA, Weinman EJ, Zeng C, Jose PA, Villar VAM. Sorting nexin 1 loss results in increased oxidative stress and hypertension. FASEB J 2020; 34:7941-7957. [PMID: 32293069 DOI: 10.1096/fj.201902448r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 03/13/2020] [Accepted: 03/28/2020] [Indexed: 12/13/2022]
Abstract
Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1-/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1 R), NADPH oxidase (NOX) subunits, D5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5 R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.
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Affiliation(s)
- Jian Yang
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Laureano D Asico
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Amber L Beitelshees
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jun B Feranil
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xiaoyan Wang
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - John E Jones
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Ines Armando
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Santiago G Cuevas
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Gary L Schwartz
- Division of Nephrology and Hypertension, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - John G Gums
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.,Department of Community Health and Family Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Arlene B Chapman
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Stephen T Turner
- Division of Nephrology and Hypertension, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Eric Boerwinkle
- Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA
| | - Rhonda M Cooper-DeHoff
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Julie A Johnson
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Robin A Felder
- Department of Pathology, The University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Edward J Weinman
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,The Department of Veterans Affairs, Baltimore, MD, USA
| | - Chunyu Zeng
- Department of Cardiology, Fujian Heart Medical Center, Fujian Medical University Union Hospital, Fujian, P.R.China.,Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China
| | - Pedro A Jose
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Van Anthony M Villar
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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Rambacher KM, Moniri NH. The β2-adrenergic receptor-ROS signaling axis: An overlooked component of β2AR function? Biochem Pharmacol 2019; 171:113690. [PMID: 31697929 DOI: 10.1016/j.bcp.2019.113690] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023]
Abstract
β2-Adrenergic receptor (β2AR) agonists are clinically used to elicit rapid bronchodilation for the treatment of bronchospasms in pulmonary diseases such as asthma and COPD, both of which exhibit characteristically high levels of reactive oxygen species (ROS); likely secondary to over-expression of ROS generating enzymes and chronically heightened inflammation. Interestingly, β2AR has long-been linked to ROS, yet the involvement of ROS in β2AR function has not been as vigorously studied as other aspects of β2AR signaling. Herein, we discuss the existing body of evidence linking β2AR activation to intracellular ROS generation and importantly, the role of ROS in regulating β2AR function. The reciprocal interplay of the β2AR and ROS appear to endow this receptor with the ability to self-regulate signaling efficacy and ligand binding, hereby unveiling a redox-axis that may be unfavorably altered in pathological states contributing to both disease progression and therapeutic drug responses.
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Affiliation(s)
- Kalyn M Rambacher
- Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA 30341, USA
| | - Nader H Moniri
- Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA 30341, USA.
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14
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Cuevas S, Villar VAM, Jose PA. Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation. THE PHARMACOGENOMICS JOURNAL 2019; 19:315-336. [PMID: 30723314 PMCID: PMC6650341 DOI: 10.1038/s41397-019-0082-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 10/19/2018] [Accepted: 12/21/2018] [Indexed: 02/08/2023]
Abstract
Hypertension is the most prevalent cause of cardiovascular disease and kidney failure, but only about 50% of patients achieve adequate blood pressure control, in part, due to inter-individual genetic variations in the response to antihypertensive medication. Significant strides have been made toward the understanding of the role of reactive oxygen species (ROS) in the regulation of the cardiovascular system. However, the role of ROS in human hypertension is still unclear. Polymorphisms of some genes involved in the regulation of ROS production are associated with hypertension, suggesting their potential influence on blood pressure control and response to antihypertensive medication. This review provides an update on the genes associated with the regulation of ROS production in hypertension and discusses the controversies on the use of antioxidants in the treatment of hypertension, including the antioxidant effects of antihypertensive drugs.
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Affiliation(s)
- Santiago Cuevas
- Center for Translational Science, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC, 20010, USA.
| | - Van Anthony M Villar
- Department of Medicine, Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, Walter G. Ross Hall, Suite 738, 2300 I Street, NW, Washington, DC, 20052, USA
| | - Pedro A Jose
- Department of Medicine, Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, Walter G. Ross Hall, Suite 738, 2300 I Street, NW, Washington, DC, 20052, USA
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15
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Wang S, Tan X, Chen P, Zheng S, Ren H, Cai J, Zhou L, Jose PA, Yang J, Zeng C. Role of Thioredoxin 1 in Impaired Renal Sodium Excretion of hD 5 R F173L Transgenic Mice. J Am Heart Assoc 2019; 8:e012192. [PMID: 30957627 PMCID: PMC6507211 DOI: 10.1161/jaha.119.012192] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/12/2019] [Indexed: 12/12/2022]
Abstract
Background Dopamine D5 receptor (D5R) plays an important role in the maintenance of blood pressure by regulating renal sodium transport. Our previous study found that human D5R mutant F173L transgenic ( hD 5 R F173L-TG) mice are hypertensive. In the present study, we aimed to investigate the mechanisms causing this renal D5R dysfunction in hD 5 R F173L-TG mice. Methods and Results Compared with wild-type D5R-TG ( hD 5 R WT-TG) mice, hD 5 R F173L-TG mice have higher blood pressure, lower basal urine flow and sodium excretion, and impaired agonist-mediated natriuresis and diuresis. Enhanced reactive oxygen species production in hD 5 R F173L-TG mice is caused, in part, by decreased expression of antioxidant enzymes, including thioredoxin 1 (Trx1). Na+-K+-ATPase activity is increased in mouse renal proximal tubule cells transfected with hD 5 R F173L, but is normalized by treatment with exogenous recombinant human Trx1 protein. Regulation of Trx1 by D5R occurs by the phospholipase C/ protein kinase C (PKC) pathway because upregulation of Trx1 expression by D5R does not occur in renal proximal tubule cells from D1R knockout mice in the presence of a phospholipase C or PKC inhibitor. Fenoldopam, a D1R and D5R agonist, stimulates PKC activity in primary renal proximal tubule cells of hD5R WT -TG mice, but not in those of hD 5 R F173L-TG mice. Hyperphosphorylation of hD5RF173L and its dissociation from Gαs and Gαq are associated with impairment of D5R-mediated inhibition of Na+-K+-ATPase activity in hD 5 R F173L-TG mice. Conclusions These suggest that hD 5 R F173L increases blood pressure, in part, by decreasing renal Trx1 expression and increasing reactive oxygen species production. Hyperphosphorylation of hD5RF173L, with its dissociation from Gαs and Gαq, is the key factor in impaired D5R function of hD 5 R F173L-TG mice.
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Affiliation(s)
- Shaoxiong Wang
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Xiaorong Tan
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Peng Chen
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Shuo Zheng
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Hongmei Ren
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Jin Cai
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Lin Zhou
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
| | - Pedro A. Jose
- Division of Renal Disease & HypertensionDepartments of Medicine and Pharmacology/PhysiologyThe George Washington University School of Medicine and Health SciencesWashingtonDC
| | - Jian Yang
- Department of Clinical NutritionThe Third Affiliated Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Chunyu Zeng
- Department of CardiologyDaping HospitalArmy Medical University of PLAChongqingP.R. China
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16
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Over-expression of a cardiac-specific human dopamine D5 receptor mutation in mice causes a dilated cardiomyopathy through ROS over-generation by NADPH oxidase activation and Nrf2 degradation. Redox Biol 2018; 19:134-146. [PMID: 30153650 PMCID: PMC6111036 DOI: 10.1016/j.redox.2018.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 07/10/2018] [Accepted: 07/12/2018] [Indexed: 12/26/2022] Open
Abstract
Dilated cardiomyopathy (DCM) is a severe disorder caused by medications or genetic mutations. D5 dopamine receptor (D5R) gene knockout (D5-/-) mice have cardiac hypertrophy and high blood pressure. To investigate the role and mechanism by which the D5R regulates cardiac function, we generated cardiac-specific human D5R F173L(hD5F173L-TG) and cardiac-specific human D5R wild-type (hD5WT-TG) transgenic mice, and H9c2 cells stably expressing hD5F173L and hD5WT. We found that cardiac-specific hD5F173L-TG mice, relative to hD5WT-TG mice, presented with DCM and increased cardiac expression of cardiac injury markers, NADPH oxidase activity, Nrf2 degradation, and activated ERK1/2/JNK pathway. H9c2-hD5F173L cells also had an increase in NADPH oxidase activity, Nrf2 degradation, and phospho-JNK (p-JNK) expression. A Nrf2 inhibitor also increased p-JNK expression in H9c2-hD5F173L cells but not in H9c2-hD5WT cells. We suggest that the D5R may play an important role in the preservation of normal heart function by inhibiting the production of reactive oxygen species, via inhibition of NADPH oxidase, Nrf2 degradation, and ERK1/2/JNK pathways.
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17
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Bhat OM, Yuan X, Li G, Lee R, Li PL. Sphingolipids and Redox Signaling in Renal Regulation and Chronic Kidney Diseases. Antioxid Redox Signal 2018; 28:1008-1026. [PMID: 29121774 PMCID: PMC5849286 DOI: 10.1089/ars.2017.7129] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 10/30/2017] [Accepted: 11/04/2017] [Indexed: 01/04/2023]
Abstract
Significance: Sphingolipids play critical roles in the membrane biology and intracellular signaling events that influence cellular behavior and function. Our review focuses on the cellular mechanisms and functional relevance of the cross talk between sphingolipids and redox signaling, which may be critically implicated in the pathogenesis of different renal diseases. Recent Advances: Reactive oxygen species (ROS) and sphingolipids can regulate cellular redox homeostasis through the regulation of NADPH oxidase, mitochondrial integrity, nitric oxide synthase (NOS), and antioxidant enzymes. Over the last two decades, there have been significant advancements in the field of sphingolipid research, and it was in 2010 for the first time that sphingolipid receptor modulator was exploited as a therapeutic in humans. The cross talk of sphingolipids with redox signaling pathways becomes an important mechanism in the development of many different diseases such as renal diseases. Critical Issues: The critical issues to be addressed in this review are how sphingolipids interact with the redox signaling pathway to regulate renal function and even result in chronic kidney diseases. Ceramide, sphingosine, and sphingosine-1-phosphate (S1P) as main signaling sphingolipids are discussed in more detail. Future Directions: Although sphingolipids and ROS may mediate or modulate cellular responses to physiological and pathological stimuli, more translational studies and mechanistic pursuit in a tissue- or cell-specific way are needed to enhance our understanding of this important topic and to develop effective therapeutic strategies to treat diseases associated with redox signaling and sphingolipid cross talk. Antioxid. Redox Signal. 28, 1008-1026.
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Affiliation(s)
- Owais M Bhat
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Xinxu Yuan
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Guangbi Li
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - RaMi Lee
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Pin-Lan Li
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
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18
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Jiang X, Chen W, Liu X, Wang Z, Liu Y, Felder RA, Gildea JJ, Jose PA, Qin C, Yang Z. The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion. PLoS One 2016; 11:e0146641. [PMID: 26751218 PMCID: PMC4709046 DOI: 10.1371/journal.pone.0146641] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 12/21/2015] [Indexed: 01/07/2023] Open
Abstract
Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other’s expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.
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Affiliation(s)
- Xiaoliang Jiang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
| | - Wei Chen
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
| | - Xing Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
| | - Zihao Wang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
| | - Yunpeng Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
| | - Robin A. Felder
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America
| | - John J. Gildea
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America
| | - Pedro A. Jose
- Division of Nephrology, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- * E-mail: (PAJ); (CQ); (ZWY)
| | - Chuan Qin
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
- * E-mail: (PAJ); (CQ); (ZWY)
| | - Zhiwei Yang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China
- CollaborativeInnovation Center for Cardiovascular Disorders, Beijing, P. R. China
- * E-mail: (PAJ); (CQ); (ZWY)
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Liu X, Wang W, Chen W, Jiang X, Zhang Y, Wang Z, Yang J, Jones JE, Jose PA, Yang Z. Regulation of blood pressure, oxidative stress and AT1R by high salt diet in mutant human dopamine D5 receptor transgenic mice. Hypertens Res 2015; 38:394-9. [PMID: 25716648 PMCID: PMC6400478 DOI: 10.1038/hr.2015.17] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/12/2015] [Accepted: 01/25/2015] [Indexed: 12/20/2022]
Abstract
Humans have dopamine D5 receptors (hD5R) with single-nucleotide polymorphisms and a diminished function. We generated hD5(F173L) cDNA that has a decreased response to D5R agonist-mediated increase in cAMP production and increased production of reactive oxygen species, relative to wild-type hD5R (hD5(WT)) cDNA expressed in Chinese hamster ovary cells. To investigate the role of hD5(F173L) in the pathogenesis of salt-sensitive hypertension, we generated transgenic mice overexpressing hD5(F173L) or hD5(WT) and fed them normal (0.8% NaCl) or high (4% NaCl) salt diet. On normal salt diet, the blood pressure, and renal NADPH oxidase activity and angiotensin type 1 receptor (AT1R) expression were higher in hD5(F173L) than hD5(WT) transgenic mice. After 2 weeks on high salt diet, the blood pressure and renal NADPH oxidase activity, but not AT1R expression, were increased in hD5(F173L) but not in hD5(WT) transgenic mice. Candesartan, an AT1R antagonist, decreased the blood pressure and NADPH oxidase activity in hD5(F173L) but not in hD5(WT) transgenic mice. We suggest that the ability of the hD5R to negatively regulate the renal NADPH oxidase activity and AT1R function may have important implications in the pathogenesis of salt-sensitive blood pressure. However, the mechanisms involved in regulating the balance of renal D5R and AT1R function in the oxidative stress-mediated salt-sensitive blood pressure remain to be determined.
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Affiliation(s)
- Xing Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
| | - Wenjie Wang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
| | - Wei Chen
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
| | - Xiaoliang Jiang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
| | - Yanrong Zhang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
| | - Zihao Wang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
| | - Jian Yang
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - John E Jones
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Pedro A Jose
- 1] Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA [2] Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Zhiwei Yang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, People's Republic China
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Choi MR, Kouyoumdzian NM, Rukavina Mikusic NL, Kravetz MC, Rosón MI, Rodríguez Fermepin M, Fernández BE. Renal dopaminergic system: Pathophysiological implications and clinical perspectives. World J Nephrol 2015; 4:196-212. [PMID: 25949933 PMCID: PMC4419129 DOI: 10.5527/wjn.v4.i2.196] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 01/22/2015] [Accepted: 02/04/2015] [Indexed: 02/06/2023] Open
Abstract
Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent.
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Abstract
Since the first demonstration of Nox enzyme expression in the kidney in the early 1990s and the subsequent identification of Nox4, or RENOX, a decade later, it has become apparent that the Nox family of reactive oxygen species (ROS) generating enzymes plays an integral role in the normal physiological function of the kidney. As our knowledge of Nox expression patterns and functions in various structures and specialized cell types within the kidney grows, so does the realization that Nox-derived oxidative stress contributes significantly to a wide variety of renal pathologies through their ability to modify lipids and proteins, damage DNA and activate transcriptional programmes. Diverse studies demonstrate key roles for Nox-derived ROS in kidney fibrosis, particularly in settings of chronic renal disease such as diabetic nephropathy. As the most abundant Nox family member in the kidney, much emphasis has been placed on the role of Nox4 in this setting. However, an ever growing body of work continues to uncover key roles for other Nox family members, not only in diabetic kidney disease, but in a diverse array of renal pathological conditions. The objective of the present review is to highlight the latest novel developments in renal Nox biology with an emphasis not only on diabetic nephropathy but many of the other renal disease contexts where oxidative stress is implicated.
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Yang S, Yang Y, Yu P, Yang J, Jiang X, Villar VAM, Sibley DR, Jose PA, Zeng C. Dopamine D1 and D5 receptors differentially regulate oxidative stress through paraoxonase 2 in kidney cells. Free Radic Res 2015; 49:397-410. [PMID: 25740199 DOI: 10.3109/10715762.2015.1006215] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The renal dopaminergic system plays an important role in the pathogenesis of hypertension. Dopamine D1-like receptors (D1R and D5R) decrease reactive oxygen species (ROS) production via inhibition of pro-oxidant enzymes such as NADPH oxidase. Paraoxonase 2 (PON2) is also involved in the inhibition of NADPH oxidase activity. Therefore, we tested the hypothesis that D1R and D5R inhibit ROS production by increasing the expression of PON2, including those in membrane microdomains. METHODS AND RESULTS PON2 colocalized with D1R and D5R in mouse renal proximal tubules (RPTs), human RPT (hRPT) cells, and HEK293 cells heterologously expressing human D1R (HEK-hD1R) or D5R (HEK-hD5R). Fenoldopam, an agonist for both D1R and D5R, increased PON2 co-immunoprecipitation with D1R and D5R in HEK-hD1R and HEK-hD5R cells, respectively. Silencing PON2 increased ROS production and NADPH oxidase activity, and impaired the inhibitory effect of fenoldopam. Fenoldopam increased PON2 protein in both lipid rafts (LRs) and non-LRs in HEK-hD1R cells, but only in non-LRs in HEK-hD5R and hRPT cells. Long-term (hrs) fenoldopam stimulation increased PON2 protein in a time-dependent manner in HEK-hD5R, but not in HEK-hD1R cells. Because the effects of fenoldopam on non-LR and total PON2 expressions were similar in HEK-hD5R and hRPT cells, additional studies were performed to determine the relationship between D5R and PON2. Renal PON2 protein was decreased in D5(-/-) mice. In hRPT cells, silencing D5R decreased PON2 expression and increased ROS production. CONCLUSIONS We conclude that D1-like receptors inhibit ROS production by altering PON2 distribution in membrane microdomains in the short-term, and by increasing PON2 expression in the long-term.
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Affiliation(s)
- S Yang
- Department of Cardiology, Daping Hospital, The Third Military Medical University , Chongqing , P. R. China
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Rukavina Mikusic NL, Kravetz MC, Kouyoumdzian NM, Della Penna SL, Rosón MI, Fernández BE, Choi MR. Signaling pathways involved in renal oxidative injury: role of the vasoactive peptides and the renal dopaminergic system. JOURNAL OF SIGNAL TRANSDUCTION 2014; 2014:731350. [PMID: 25436148 PMCID: PMC4243602 DOI: 10.1155/2014/731350] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 10/16/2014] [Indexed: 12/24/2022]
Abstract
The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation.
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Affiliation(s)
- N. L. Rukavina Mikusic
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
| | - M. C. Kravetz
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
| | - N. M. Kouyoumdzian
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
| | - S. L. Della Penna
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
| | - M. I. Rosón
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
| | - B. E. Fernández
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
| | - M. R. Choi
- Department of Pathophysiology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, CONICET, INFIBIOC, 1113 Buenos Aires, Argentina
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Yu P, Sun M, Villar VAM, Zhang Y, Weinman EJ, Felder RA, Jose PA. Differential dopamine receptor subtype regulation of adenylyl cyclases in lipid rafts in human embryonic kidney and renal proximal tubule cells. Cell Signal 2014; 26:2521-9. [PMID: 25049074 DOI: 10.1016/j.cellsig.2014.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 07/09/2014] [Indexed: 01/11/2023]
Abstract
Dopamine D1-like receptors (D1R and D5R) stimulate adenylyl cyclase (AC) activity, whereas the D2-like receptors (D2, D3 and D4) inhibit AC activity. D1R, but not the D5R, has been reported to regulate AC activity in lipid rafts (LRs). We tested the hypothesis that D1R and D5R differentially regulate AC activity in LRs using human embryonic kidney (HEK) 293 cells heterologously expressing human D1 or D5 receptor (HEK-hD1R or HEK-hD5R) and human renal proximal tubule (hRPT) cells that endogenously express D1R and D5R. Of the AC isoforms expressed in HEK and hRPT cells (AC3, AC5, AC6, AC7, and AC9), AC5/6 was distributed to a greater extent in LRs than non-LRs in HEK-hD1R (84.5±2.3% of total), HEK-hD5R (68.9±3.1% of total), and hRPT cells (66.6 ± 2.2% of total) (P<0.05, n=4/group). In HEK-hD1R cells, the D1-like receptor agonist fenoldopam (1 μM/15 min) increased AC5/6 protein (+17.2 ± 3.9% of control) in LRs but decreased it in non-LRs (-47.3±5.3% of control) (P<0.05, vs. control, n=4/group). By contrast, in HEK-hD5R cells, fenoldopam increased AC5/6 protein in non-LRs (+67.1 ± 5.3% of control, P<0.006, vs. control, n=4) but had no effect in LRs. In hRPT cells, fenoldopam increased AC5/6 in LRs but had little effect in non-LRs. Disruption of LRs with methyl-β-cyclodextrin decreased basal AC activity in HEK-D1R (-94.5 ± 2.0% of control) and HEK-D5R cells (-87.1 ± 4.6% of control) but increased it in hRPT cells (6.8±0.5-fold). AC6 activity was stimulated to a greater extent by D1R than D5R, in agreement with the greater colocalization of AC5/6 with D1R than D5R in LRs. We conclude that LRs are essential not only for the proper membrane distribution and maintenance of AC5/6 activity but also for the regulation of D1R- and D5R-mediated AC signaling.
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Affiliation(s)
- Peiying Yu
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Min Sun
- Department of Biological Sciences, School of Life Science, Anhui University, Anhui, China
| | - Van Anthony M Villar
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Yanrong Zhang
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Edward J Weinman
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Robin A Felder
- Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22903, United States
| | - Pedro A Jose
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States
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Yu P, Han W, Villar VAM, Yang Y, Lu Q, Lee H, Li F, Quinn MT, Gildea JJ, Felder RA, Jose PA. Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells. Redox Biol 2014; 2:570-9. [PMID: 24688893 PMCID: PMC3969603 DOI: 10.1016/j.redox.2014.01.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Revised: 01/28/2014] [Accepted: 01/30/2014] [Indexed: 12/22/2022] Open
Abstract
NADPH oxidases are the major sources of reactive oxygen species in cardiovascular, neural, and kidney cells. The NADPH oxidase 5 (NOX5) gene is present in humans but not rodents. Because Nox isoforms in renal proximal tubules (RPTs) are involved in the pathogenesis of hypertension, we tested the hypothesis that NOX5 is differentially expressed in RPT cells from normotensive (NT) and hypertensive subjects (HT). We found that NOX5 mRNA, total NOX5 protein, and apical membrane NOX5 protein were 4.2±0.7-fold, 5.2±0.7-fold, and 2.8±0.5-fold greater in HT than NT. Basal total NADPH oxidase activity was 4.5±0.2-fold and basal NOX5 activity in NOX5 immunoprecipitates was 6.2±0.2-fold greater in HT than NT (P=<0.001, n=6-14/group). Ionomycin increased total NOX and NOX5 activities in RPT cells from HT (P<0.01, n=4, ANOVA), effects that were abrogated by pre-treatment of the RPT cells with diphenylene-iodonium or superoxide dismutase. Silencing NOX5 using NOX5-siRNA decreased NADPH oxidase activity (-45.1±3.2% vs. mock-siRNA, n=6-8) in HT. D1-like receptor stimulation decreased NADPH oxidase activity to a greater extent in NT (-32.5±1.8%) than HT (-14.8±1.8). In contrast to the marked increase in expression and activity of NOX5 in HT, NOX1 mRNA and protein were minimally increased in HT, relative to NT; total NOX2 and NOX4 proteins were not different between HT and NT, while the increase in apical RPT cell membrane NOX1, NOX2, and NOX4 proteins in HT, relative to NT, was much less than those observed with NOX5. Thus, we demonstrate, for the first time, that NOX5 is expressed in human RPT cells and to greater extent than the other Nox isoforms in HT than NT. We suggest that the increased expression of NOX5, which may be responsible for the increased oxidative stress in RPT cells in human essential hypertension, is caused, in part, by a defective renal dopaminergic system.
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Affiliation(s)
- Peiying Yu
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Weixing Han
- Department of Cardiovascular Medicine, The First Hospital Affiliated to Anhui Medical University, Hefei, Anhui, PR China
| | - Van Anthony M Villar
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yu Yang
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Quansheng Lu
- Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA
| | - Hewang Lee
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Fengmin Li
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mark T Quinn
- Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT, USA
| | - John J Gildea
- Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - Robin A Felder
- Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - Pedro A Jose
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA ; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Gildea JJ, Shah IT, Van Sciver RE, Israel JA, Enzensperger C, McGrath HE, Jose PA, Felder RA. The cooperative roles of the dopamine receptors, D1R and D5R, on the regulation of renal sodium transport. Kidney Int 2014; 86:118-26. [PMID: 24552847 PMCID: PMC4077925 DOI: 10.1038/ki.2014.5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/27/2013] [Accepted: 12/12/2013] [Indexed: 02/07/2023]
Abstract
Determining the individual roles of the two dopamine D1-like receptors (D1R and D5R) on sodium transport in the human renal proximal tubule has been complicated by their structural and functional similarity. Here we used a novel D5R-selective antagonist (LE-PM436) and D1R or D5R-specific gene silencing to determine second messenger coupling pathways and heterologous receptor interaction between the two receptors. D1R and D5R co-localized in renal proximal tubule cells and physically interact, as determined by co-immunoprecipitation and FRET microscopy. Stimulation of renal proximal tubule cells with fenoldopam (D1R/D5R agonist) led to both adenylyl cyclase and phospholipase C (PLC) activation using real-time FRET biosensors ICUE3 and CYPHR, respectively. Fenoldopam increased cAMP accumulation and PLC activity and inhibited both NHE3 and NaKATPase activities. LE-PM436 and D5R siRNA blocked the fenoldopam-stimulated PLC pathway but not cAMP accumulation, while D1R siRNA blocked both fenoldopam-stimulated cAMP accumulation and PLC signaling. Either D1R or D5R siRNA, or LE-PM436 blocked the fenoldopam dependent inhibition of sodium transport. Further studies using the cAMP-selective D1R/D5R agonist SKF83822 and PLC-selective D1R/D5R agonist SKF83959 confirmed the cooperative influence of the two pathways on sodium transport. Thus, D1R and D5R interact in the inhibition of NHE3 and NaKATPase activity, the D1R primarily by cAMP, while the D1R/D5R heteromer modulates the D1R effect through a PLC pathway.
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Affiliation(s)
- John J Gildea
- The University of Virginia Health System, Department of Pathology, Charlottesville, Virginia, USA
| | - Ishan T Shah
- The University of Virginia Health System, Department of Pathology, Charlottesville, Virginia, USA
| | - Robert E Van Sciver
- The University of Virginia Health System, Department of Pathology, Charlottesville, Virginia, USA
| | - Jonathan A Israel
- The University of Virginia Health System, Department of Pathology, Charlottesville, Virginia, USA
| | - Christoph Enzensperger
- Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universität Jena, Jena, Germany
| | - Helen E McGrath
- The University of Virginia Health System, Department of Pathology, Charlottesville, Virginia, USA
| | - Pedro A Jose
- University of Maryland School of Medicine, Departments of Medicine and Physiology, Baltimore, Maryland, USA
| | - Robin A Felder
- The University of Virginia Health System, Department of Pathology, Charlottesville, Virginia, USA
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27
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Aging-related dysregulation of dopamine and angiotensin receptor interaction. Neurobiol Aging 2014; 35:1726-38. [PMID: 24529758 DOI: 10.1016/j.neurobiolaging.2014.01.017] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 01/10/2014] [Accepted: 01/13/2014] [Indexed: 12/22/2022]
Abstract
It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging.
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Abstract
SIGNIFICANCE Renal oxidative stress can be a cause, a consequence, or more often a potentiating factor for hypertension. Increased reactive oxygen species (ROS) in the kidney have been reported in multiple models of hypertension and related to renal vasoconstriction and alterations of renal function. Nicotinamide adenine dinucleotide phosphate oxidase is the central source of ROS in the hypertensive kidney, but a defective antioxidant system also can contribute. RECENT ADVANCES Superoxide has been identified as the principal ROS implicated for vascular and tubular dysfunction, but hydrogen peroxide (H2O2) has been implicated in diminishing preglomerular vascular reactivity, and promoting medullary blood flow and pressure natriuresis in hypertensive animals. CRITICAL ISSUES AND FUTURE DIRECTIONS Increased renal ROS have been implicated in renal vasoconstriction, renin release, activation of renal afferent nerves, augmented contraction, and myogenic responses of afferent arterioles, enhanced tubuloglomerular feedback, dysfunction of glomerular cells, and proteinuria. Inhibition of ROS with antioxidants, superoxide dismutase mimetics, or blockers of the renin-angiotensin-aldosterone system or genetic deletion of one of the components of the signaling cascade often attenuates or delays the onset of hypertension and preserves the renal structure and function. Novel approaches are required to dampen the renal oxidative stress pathways to reduced O2(-•) rather than H2O2 selectivity and/or to enhance the endogenous antioxidant pathways to susceptible subjects to prevent the development and renal-damaging effects of hypertension.
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Affiliation(s)
- Magali Araujo
- Hypertension, Kidney and Vascular Research Center, Georgetown University , Washington, District of Columbia
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29
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Armando I, Villar VAM, Jones JE, Lee H, Wang X, Asico LD, Yu P, Yang J, Escano CS, Pascua-Crusan AM, Felder RA, Jose PA. Dopamine D3 receptor inhibits the ubiquitin-specific peptidase 48 to promote NHE3 degradation. FASEB J 2013; 28:1422-34. [PMID: 24308971 DOI: 10.1096/fj.13-243840] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The dopamine D3 receptor (D3R) is crucial in the regulation of blood pressure and sodium balance, in that Drd3 gene ablation in mice results in hypertension and failure to excrete a dietary salt load. The mechanism responsible for the renal sodium retention in these mice is largely unknown. We now offer and describe a novel mechanism by which D3R decreases sodium transport in the long term by inhibiting the deubiquitinylating activity of ubiquitin-specific peptidase 48 (USP48), thereby promoting Na(+)-H(+) exchanger (NHE)-3 degradation. We found that stimulation with the D3R-specific agonist PD128907 (1 μM, 30 min) promoted the interaction and colocalization among D3R, NHE3, and USP48; inhibited USP48 activity (-35±6%, vs. vehicle), resulting in increased ubiquitinylated NHE3 (+140±10%); and decreased NHE3 expression (-50±9%) in human renal proximal tubule cells (hRPTCs). USP48 silencing decreased NHE3's half-life (USP48 siRNA t1/2=6.1 h vs. vehicle t1/2=12.9 h), whereas overexpression of USP48 increased NHE3 half-life (t1/2=21.8 h), indicating that USP48 protects NHE3 from degradation via deubiquitinylation. USP48 accounted for ∼30% of the total deubiquitinylating activity in these cells. Extending our studies in vivo, we found that pharmacologic blockade of D3R via the D3R-specific antagonist GR103691 (1 μg/kg/min, 4 d) in C57Bl/6J mice increased renal NHE3 expression (+310±15%, vs. vehicle), whereas an innovative kidney-restricted Usp48 silencing via siRNA (3 μg/d, 7 d) increased ubiquitinylated NHE3 (+250±30%, vs. controls), decreased total NHE3 (-23±2%), and lowered blood pressure (-24±2 mm Hg), compared with that in control mice that received either the vehicle or nonsilencing siRNA. Our data demonstrate a crucial role for the dynamic interaction between D3R and USP48 in the regulation of NHE3 expression and function.
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Affiliation(s)
- Ines Armando
- 2Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, 20 Penn St., HSF II, Ste. S003C, Baltimore, MD, USA 21201,
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Renal dopamine receptors, oxidative stress, and hypertension. Int J Mol Sci 2013; 14:17553-72. [PMID: 23985827 PMCID: PMC3794741 DOI: 10.3390/ijms140917553] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 08/09/2013] [Accepted: 08/12/2013] [Indexed: 12/22/2022] Open
Abstract
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.
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Wang X, Escano CS, Asico L, Jones JE, Barte A, Lau YS, Jose PA, Armando I. Upregulation of renal D5 dopamine receptor ameliorates the hypertension in D3 dopamine receptor-deficient mice. Hypertension 2013; 62:295-301. [PMID: 23753418 DOI: 10.1161/hypertensionaha.113.01483] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
D3 dopamine receptor (D3R)-deficient mice have renin-dependent hypertension associated with sodium retention, but the hypertension is mild. To determine whether any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3(-/-)) and heterozygous (D3(+/-)) knockout mice and their wild-type (D3(+/+)) littermates. The renal immunohistochemistry and protein expression of D5R were increased (n=5/group) in D3(-/-) mice; renal D4R protein expression was decreased, whereas renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3(+/-) (n=5/group) relative to D3(+/+) mice, whereas D1R, D2R, and D4R protein expressions were similar in D3(+/-) and D3(+/+) mice. The increase in renal D5R protein expression was abolished when D3(-/-) mice were fed a high-salt diet. Treatment with the D1-like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3(-/-) but not D3(+/+) mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3(-/-) mice. The renal D5R protein upregulation was not caused by increased transcription because renal mRNA expression of D5R was similar in D3(-/-) and D3(+/+) mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3(-/-) mice.
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Affiliation(s)
- Xiaoyan Wang
- Department of Medicine, University of Maryland, School of Medicine, 20 Penn St, Baltimore, MD 21201, USA.
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D5 dopamine receptor decreases NADPH oxidase, reactive oxygen species and blood pressure via heme oxygenase-1. Hypertens Res 2013; 36:684-90. [PMID: 23425954 DOI: 10.1038/hr.2013.9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 12/06/2012] [Accepted: 12/21/2012] [Indexed: 02/07/2023]
Abstract
D5 dopamine receptor (D5R) knock-out mice (D5(-/-)) have a higher blood pressure (BP) and higher reactive oxygen species (ROS) production than their D5R wild-type littermates (D5(+/+)). We tested the hypothesis that the high BP and increased ROS production in D5(-/-) mice may be caused by decreased heme oxygenase-1 (HO-1) expression and activity. We found that renal HO-1 protein expression and HO enzyme activity were decreased (65 and 50%, respectively) in D5(-/-) relative to D5(+/+) mice. A 24 h of administration of hemin, an HO-1 inducer, increased HO-1 expression and HO activity (6.8- and 1.9-fold, respectively) and normalized the increased ROS production and BP in D5(-/-) mice. Expression of HO-1 protein and HO activity were increased (2.3- and 1.5-fold, respectively) in HEK cells that heterologously expressed human wild-type D5R (HEK-hD5R), but not the empty vector-transfected HEK-293 cells. Fenoldopam (Fen), a D5R agonist, increased HO activity (3 h), HO-1 protein expression, HO-1 and D5R colocalization and co-immunoprecipitation in HEK-hD5R cells. Cellular NADPH oxidase activity was decreased by 35% in HEK-hD5R that was abrogated with silencing of the heme oxygenase 1 gene (HMOX1). HMOX1 siRNA also impaired the ability of Fen to decrease NADPH oxidase activity in HEK-hD5R cells. In summary, the D5R positively regulates HO-1 through direct protein/protein interaction in the short-term and by increasing HO-1 protein expression in the long-term. The impaired D5R regulation of HO-1 and ROS production contributes to the pathogenesis of hypertension in D5(-/-) mice.
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Hu MC, Di Sole F, Zhang J, McLeroy P, Moe OW. Chronic regulation of the renal Na(+)/H(+) exchanger NHE3 by dopamine: translational and posttranslational mechanisms. Am J Physiol Renal Physiol 2013; 304:F1169-80. [PMID: 23427139 DOI: 10.1152/ajprenal.00630.2012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The intrarenal autocrine/paracrine dopamine (DA) system contributes to natriuresis in response to both acute and chronic Na(+) loads. While the acute DA effect is well described, how DA induces natriuresis chronically is not known. We used an animal and a cell culture model to study the chronic effect of DA on a principal renal Na(+) transporter, Na(+)/H(+) exchanger-3 (NHE3). Intraperitoneal injection of Gludopa in rats for 2 days elevated DA excretion and decreased total renal cortical and apical brush-border NHE3 antigen. Chronic treatment of an opossum renal proximal cell line with DA decreased NHE3 activity, cell surface and total cellular NHE3 antigen, but not NHE3 transcript. The decrease in NHE3 antigen was dose and time dependent with maximal inhibition at 16-24 h and half maximal effect at 3 × 10(-7) M. This is in contradistinction to the acute effect of DA on NHE3 (half maximal at 2 × 10(-6) M), which was not associated with changes in total cellular NHE3 protein. The DA-induced decrease in total NHE3 protein was associated with decrease in NHE3 translation and mediated by cis-sequences in the NHE3 5'-untranslated region. DA also decreased cell surface and total cellular NHE3 protein half-life. The DA-induced decrease in total cellular NHE3 was partially blocked by proteasome inhibition but not by lysosome inhibition, and DA increased ubiquitylation of total and surface NHE3. In summary, chronic DA inhibits NHE3 with mechanisms distinct from its acute action and involves decreased NHE3 translation and increased NHE3 degradation, which are novel mechanisms for NHE3 regulation.
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Affiliation(s)
- Ming Chang Hu
- Dept. of Internal Medicine, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8885, USA
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Li PL, Zhang Y. Cross talk between ceramide and redox signaling: implications for endothelial dysfunction and renal disease. Handb Exp Pharmacol 2013:171-97. [PMID: 23563657 DOI: 10.1007/978-3-7091-1511-4_9] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent studies have demonstrated that cross talk between ceramide and redox signaling modulates various cell activities and functions and contributes to the development of cardiovascular diseases and renal dysfunctions. Ceramide triggers the generation of reactive oxygen species (ROS) and increases oxidative stress in many mammalian cells and animal models. On the other hand, inhibition of ROS-generating enzymes or treatment of antioxidants impairs sphingomyelinase activation and ceramide production. As a mechanism, ceramide-enriched signaling platforms, special cell membrane rafts (MR) (formerly lipid rafts), provide an important microenvironment to mediate the cross talk of ceramide and redox signaling to exert a corresponding regulatory role on cell and organ functions. In this regard, activation of acid sphingomyelinase and generation of ceramide mediate the formation of ceramide-enriched membrane platforms, where transmembrane signals are transmitted or amplified through recruitment, clustering, assembling, or integration of various signaling molecules. A typical such signaling platform is MR redox signaling platform that is centered on ceramide production and aggregation leading to recruitment and assembling of NADPH oxidase to form an active complex in the cell plasma membrane. This redox signaling platform not only conducts redox signaling or regulation but also facilitates a feedforward amplification of both ceramide and redox signaling. In addition to this membrane MR redox signaling platform, the cross talk between ceramide and redox signaling may occur in other cell compartments. This book chapter focuses on the molecular mechanisms, spatial-temporal regulations, and implications of this cross talk between ceramide and redox signaling, which may provide novel insights into the understanding of both ceramide and redox signaling pathways.
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Affiliation(s)
- Pin-Lan Li
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
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Villar VAM, Jones JE, Armando I, Asico LD, Escano CS, Lee H, Wang X, Yang Y, Pascua-Crusan AM, Palmes-Saloma CP, Felder RA, Jose PA. Sorting nexin 1 loss results in D5 dopamine receptor dysfunction in human renal proximal tubule cells and hypertension in mice. J Biol Chem 2012; 288:152-63. [PMID: 23152498 DOI: 10.1074/jbc.m112.428458] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D(5)R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D(5)R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D(5)R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D(5)R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D(5)R trafficking and that SNX1 depletion results in D(5)R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension.
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Affiliation(s)
- Van Anthony M Villar
- Center for Molecular Physiology Research, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
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Chugh G, Pokkunuri I, Asghar M. Renal dopamine and angiotensin II receptor signaling in age-related hypertension. Am J Physiol Renal Physiol 2012; 304:F1-7. [PMID: 23097467 DOI: 10.1152/ajprenal.00441.2012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Kidneys play a vital role in long-term regulation of blood pressure. This is achieved by actions of many renal and nonrenal factors acting on the kidney that help maintain the body's water and electrolyte balance and thus control blood pressure. Several endogenously formed or circulating hormones/peptides, by acting within the kidney, regulate fluid and water homeostasis and blood pressure. Dopamine and angiotensin II are the two key renal factors that, via acting on their receptors and counterregulating each other's function, maintain water and sodium balance. In this review, we provide recent advances in the signaling cascades of these renal receptors, especially at the level of their cross talk, and discuss their roles in blood pressure regulation in the aging process.
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Affiliation(s)
- Gaurav Chugh
- Heart and Kidney Institute, College of Pharmacy, Univ. of Houston, Houston, TX 77204, USA
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37
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Zhang MZ, Yao B, Yang S, Yang H, Wang S, Fan X, Yin H, Fogo AB, Moeckel GW, Harris RC. Intrarenal dopamine inhibits progression of diabetic nephropathy. Diabetes 2012; 61:2575-84. [PMID: 22688335 PMCID: PMC3447896 DOI: 10.2337/db12-0046] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The kidney has a local intrarenal dopaminergic system, and in the kidney, dopamine modulates renal hemodynamics, inhibits salt and fluid reabsorption, antagonizes the renin-angiotensin system, and inhibits oxidative stress. The current study examined the effects of alterations in the intrarenal dopaminergic system on kidney structure and function in models of type 1 diabetes. We studied catechol-O-methyl-transferase (COMT)(-/-) mice, which have increased renal dopamine production due to decreased dopamine metabolism, and renal transplantation was used to determine whether the effects seen with COMT deficiency were kidney-specific. To determine the effects of selective inhibition of intrarenal dopamine production, we used mice with proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)). Compared with wild-type diabetic mice, COMT(-/-) mice had decreased hyperfiltration, decreased macula densa cyclooxygenase-2 expression, decreased albuminuria, decreased glomerulopathy, and inhibition of expression of markers of inflammation, oxidative stress, and fibrosis. These differences were also seen in diabetic mice with a transplanted kidney from COMT(-/-) mice. In contrast, diabetic ptAADC(-/-) mice had increased nephropathy. Our study demonstrates an important role of the intrarenal dopaminergic system to modulate the development and progression of diabetic kidney injury and indicate that the decreased renal dopamine production may have important consequences in the underlying pathogenesis of diabetic nephropathy.
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Affiliation(s)
- Ming-Zhi Zhang
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Corresponding author: Ming-Zhi Zhang, , or Raymond C. Harris,
| | - Bing Yao
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Shilin Yang
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Haichun Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Suwan Wang
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Xiaofeng Fan
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Huiyong Yin
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Agnes B. Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Gilbert W. Moeckel
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Raymond C. Harris
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
- Nashville Veterans Affairs Hospital, Nashville, Tennessee
- Corresponding author: Ming-Zhi Zhang, , or Raymond C. Harris,
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Bókkon I, Antal I. Schizophrenia: redox regulation and volume neurotransmission. Curr Neuropharmacol 2012; 9:289-300. [PMID: 22131938 PMCID: PMC3131720 DOI: 10.2174/157015911795596504] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2010] [Revised: 05/30/2010] [Accepted: 06/04/2010] [Indexed: 02/08/2023] Open
Abstract
Here, we show that volume neurotransmission and the redox property of dopamine, as well as redox-regulated processes at glutamate receptors, can contribute significantly to our understanding of schizophrenia. Namely, volume neurotransmission may play a key role in the development of dysconnectivity between brain regions in schizophrenic patients, which can cause abnormal modulation of NMDA-dependent synaptic plasticity and produce local paroxysms in deafferented neural areas. During synaptic transmission, neuroredox regulations have fundamental functions, which involve the excellent antioxidant properties and nonsynaptic neurotransmission of dopamine. It is possible that the effect of redox-linked volume neurotransmission (diffusion) of dopamine is not as exact as communication by the classical synaptic mechanism, so approaching the study of complex schizophrenic mechanisms from this perspective may be beneficial. However, knowledge of redox signal processes, including the sources and molecular targets of reactive species, is essential for understanding the physiological and pathophysiological signal pathways in cells and the brain, as well as for pharmacological design of various types of new drugs.
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Affiliation(s)
- I Bókkon
- Doctoral School of Pharmaceutical and Pharmacological Sciences, Semmelweis University, Budapest, Hungary
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Yang Y, Zhang Y, Cuevas S, Villar VA, Escano C, Asico L, Yu P, Grandy DK, Felder RA, Armando I, Jose PA. Paraoxonase 2 decreases renal reactive oxygen species production, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of NADPH oxidase. Free Radic Biol Med 2012; 53:437-46. [PMID: 22634053 PMCID: PMC3408834 DOI: 10.1016/j.freeradbiomed.2012.05.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 04/20/2012] [Accepted: 05/09/2012] [Indexed: 12/22/2022]
Abstract
The dopamine D(2) receptor (D(2)R) regulates renal reactive oxygen species (ROS) production, and impaired D(2)R function results in ROS-dependent hypertension. Paraoxonase 2 (PON2), which belongs to the paraoxonase gene family, is expressed in various tissues, acting to protect against cellular oxidative stress. We hypothesized that PON2 may be involved in preventing excessive renal ROS production and thus may contribute to maintenance of normal blood pressure. Moreover, D(2)R may decrease ROS production, in part, through regulation of PON2. D(2)R colocalized with PON2 in the brush border of mouse renal proximal tubules. Renal PON2 protein was decreased (-33±6%) in D(2)(-/-) relative to D(2)(+/+) mice. Renal subcapsular infusion of PON2 siRNA decreased PON2 protein expression (-55%), increased renal oxidative stress (2.2-fold), associated with increased renal NADPH oxidase expression (Nox1, 1.9-fold; Nox2, 2.9-fold; and Nox4, 1.6-fold) and activity (1.9-fold), and elevated arterial blood pressure (systolic, 134±5 vs 93±6mmHg; diastolic, 97±4 vs 65±7mmHg; mean 113±4 vs 75±7mmHg). To determine the relevance of the PON2 and D(2)R interaction in humans, we studied human renal proximal tubule cells. Both D(2)R and PON2 were found in nonlipid and lipid rafts and physically interacted with each other. Treatment of these cells with the D(2)R/D(3)R agonist quinpirole (1μM, 24h) decreased ROS production (-35±6%), associated with decreased NADPH oxidase activity (-32±3%) and expression of Nox2 (-41±7%) and Nox4 (-47±8%) protein, and increased expression of PON2 mRNA (2.1-fold) and protein (1.6-fold) at 24h. Silencing PON2 (siRNA, 10nM, 48h) not only partially prevented the quinpirole-induced decrease in ROS production by 36%, but also increased basal ROS production (1.3-fold), which was associated with an increase in NADPH oxidase activity (1.4-fold) and expression of Nox2 (2.1-fold) and Nox4 (1.8-fold) protein. Inhibition of NADPH oxidase with diphenylene iodonium (10μM/30 min) inhibited the increase in ROS production caused by PON2 silencing. Our results suggest that renal PON2 is involved in the inhibition of renal NADPH oxidase activity and ROS production and contributes to the maintenance of normal blood pressure. PON2 is positively regulated by D(2)R and may, in part, mediate the inhibitory effect of renal D(2)R on NADPH oxidase activity and ROS production.
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Affiliation(s)
- Yu Yang
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - Yanrong Zhang
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - Santiago Cuevas
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - Van Anthony Villar
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - Crisanto Escano
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - Laureano Asico
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - Peiying Yu
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
| | - David K. Grandy
- Departments of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR 97239
| | - Robin A. Felder
- Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22908
| | - Ines Armando
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
- Corresponding author. Fax: 202-476-6582, (I.Armando)
| | - Pedro A. Jose
- Center for Molecular Physiology Research, Children's National Medical Center, George Washington University, Washington, DC 20010
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Abstract
There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.
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Affiliation(s)
- Raymond C Harris
- Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling. Int J Nephrol 2012; 2012:381320. [PMID: 22518311 PMCID: PMC3299271 DOI: 10.1155/2012/381320] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 11/07/2011] [Indexed: 01/11/2023] Open
Abstract
The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS)-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT) sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS) are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase activity, its signaling, fibrosis, and RPT sodium reabsorption.
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Huang H, Ren H, Chen C, Wang X, Yang J, Han Y, He D, Zhou L, Asico LD, Jose PA, Zeng C. D3 dopamine receptor regulation of D5 receptor expression and function in renal proximal tubule cells. Hypertens Res 2012; 35:639-47. [PMID: 22297482 DOI: 10.1038/hr.2012.11] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dopamine receptor, via D(1)-like and D(2)-like receptors, increases sodium excretion in kidney. We have reported positive interactions between D(3) and D(1) receptors in renal proximal tubule (RPT) cells. These reports, however do not preclude that there may be also interaction between D(3) and D(5) receptors, because of the lack of selective D(1) and D(5) receptor agonists or antagonists. We hypothesize that D(3) receptors can regulate D(5) receptors, and that D(3) receptor regulation of D(5) receptors in RPTs is impaired in spontaneously hypertensive rats (SHRs). It showed that a D(3) receptor agonist, PD128907, by the activation of protein kinase C activity, increased the expression of D(5) receptors in a concentration- and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. The stimulatory effect of the D(3) receptor on D(5) receptor expression was impaired in RPT cells from SHRs. The effect of D(3) receptor on D(5) receptor is functionally relevant; stimulation of D(5) receptor decreases Na(+)-K(+) adenosine triphosphatase (ATPase) activity in WKY cells. Pretreatment with D(3) receptor agonist for 24 h enhances the D(5) receptor expression and D(5) receptor-mediated inhibitory effect on Na(+)-K(+) ATPase activity in WKY cells, but decreases them in SHR cells. The effect of D(3) receptor on D(5) receptor expression and function was also confirmed in the D(5) receptor-transfected HEK293 cells. It indicates that activation of D(3) receptor increases D(5) receptor expression and function. Altered regulation of D(3) receptor on D(5) receptors may have a role in the pathogenesis of hypertension.
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Affiliation(s)
- Hefei Huang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China
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Bókkon I, Till A, Grass F, Erdöfi Szabó A. Phantom pain reduction by low-frequency and low-intensity electromagnetic fields. Electromagn Biol Med 2012; 30:115-27. [PMID: 21861690 DOI: 10.3109/15368378.2011.596246] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Although various treatments have been presented for phantom pain, there is little proof supporting the benefits of pharmacological treatments, surgery or interventional techniques, electroconvulsive therapy, electrical nerve stimulation, far infrared ray therapy, psychological therapies, etc. Here, we report the preliminary results for phantom pain reduction by low-frequency and intensity electromagnetic fields under clinical circumstances. Our method is called as Electromagnetic-Own-Signal-Treatment (EMOST). Fifteen people with phantom limb pain participated. The patients were treated using a pre-programmed, six sessions. Pain intensity was quantified upon admission using a 0-10 verbal numerical rating scale. Most of the patients (n = 10) reported a marked reduction in the intensity of phantom limb pain. Several patients also reported about improvement in their sleep and mood quality, or a reduction in the frequency of phantom pain after the treatments. No improvements in the reduction of phantom limb pain or sleep and mood improvement were reported in the control group (n = 5). Our nonlinear electromagnetic EMOST method may be a possible therapeutic application in the reduction of phantom limb pain. Here, we also suggest that some of the possible effects of the EMOST may be achieved via the redox balance of the body and redox-related neural plasticity.
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Affiliation(s)
- István Bókkon
- Doctoral School of Pharmaceutical and Pharmacological Sciences, Semmelweis University , Budapest , Hungary.
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Cuevas S, Zhang Y, Yang Y, Escano C, Asico L, Jones JE, Armando I, Jose PA. Role of renal DJ-1 in the pathogenesis of hypertension associated with increased reactive oxygen species production. Hypertension 2012; 59:446-52. [PMID: 22215708 DOI: 10.1161/hypertensionaha.111.185744] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The D(2) dopamine receptor (D(2)R) is important in the pathogenesis of essential hypertension. We have already reported that systemic deletion of the D(2)R gene in mice results in reactive oxygen species (ROS)-dependent hypertension, suggesting that the D(2)R has antioxidant effects. However, the mechanism of this effect is unknown. DJ-1 is a protein that has antioxidant properties. D(2)R and DJ-1 are expressed in the mouse kidney and colocalize and coimunoprecipitate in mouse renal proximal tubule cells. We hypothesized that D(2)Rs regulate renal ROS production in the kidney through regulation of DJ-1 expression or function. Heterozygous D(2)(+/-) mice have increased blood pressure, urinary 8-isoprostanes, and renal Nox 4 expression, but decreased renal DJ-1 expression. Silencing D(2)R expression in mouse renal proximal tubule cells increases ROS production and decreases the expression of DJ-1. Conversely, treatment of these cells with a D(2)R agonist increases DJ-1 expression and decreases Nox 4 expression and NADPH oxidase activity, effects that are partially blocked by a D(2)R antagonist. Silencing DJ-1 expression in mouse renal proximal tubule cells increases ROS production and Nox 4 expression. Selective renal DJ-1 silencing by the subcapsular infusion of DJ-1 siRNA in mice increases blood pressure, renal Nox4 expression, and NADPH oxidase activity. These results suggest that the inhibitory effects of D(2)R on renal ROS production are at least, in part, mediated by a positive regulation of DJ-1 expression/function and that DJ-1 may have a role in the prevention of hypertension associated with increased ROS production.
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Affiliation(s)
- Santiago Cuevas
- Center for Molecular Physiology Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA.
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Guo Y, Jose PA. C-terminal di-leucine motif of dopamine D₁ receptor plays an important role in its plasma membrane trafficking. PLoS One 2011; 6:e29204. [PMID: 22206002 PMCID: PMC3242775 DOI: 10.1371/journal.pone.0029204] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Accepted: 11/22/2011] [Indexed: 12/12/2022] Open
Abstract
The dopamine D1 receptor (D1R), a G protein-coupled receptor, plays a critical role in regulating blood pressure through its actions on renal hemodynamics and epithelial ion transport, which are highly linked to its intracellular trafficking. In this study, we generated a series of C-terminal mutants of D1R that were tagged with or without enhanced yellow fluorescent protein, and analyzed the consequences of these mutants on the plasma membrane trafficking of D1R and cyclic AMP response to D1R stimulation. D1R with mutations within the endocytic recycling signal (amino acid residues 360–382) continued to be functional, albeit decreased relative to wild-type D1R. Mutation of the palmitoylation site (347C>S) of D1R did not impair its trafficking to the plasma membrane, but abolished its ability to increase cyclic AMP accumulation. In contrast, replacement of di-leucines (344–345L>A) by alanines resulted in the retention of D1R in the early endosome, decreased its glycosylation, and prevented its targeting to the plasma membrane. Our studies suggest that di-L motif at the C-terminus of D1R is critical for the glycosylation and cell surface targeting of D1R.
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Affiliation(s)
- Yan Guo
- Center for Molecular Physiology Research, Children's National Medical Center, Washington, D.C, United States of America.
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46
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Yang S, Yao B, Zhou Y, Yin H, Zhang MZ, Harris RC. Intrarenal dopamine modulates progressive angiotensin II-mediated renal injury. Am J Physiol Renal Physiol 2011; 302:F742-9. [PMID: 22169008 DOI: 10.1152/ajprenal.00583.2011] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
It is well-recognized that excessive angiotensin II (ANG II) can mediate progressive renal injury. Previous studies by us and others have indicated that dopamine may modulate actions of ANG II in the kidney. The current studies investigated whether altering intrarenal dopamine levels affected ANG II-mediated renal fibrosis. We utilized a model of increased intrarenal dopamine, catechol-O-methyl-transferase knockout (COMT KO) mice, which have increased kidney dopamine levels due to deletion of a major intrarenal dopamine-metabolizing enzyme. In wild-type mice, chronic ANG II infusion increased renal expression of both of the major dopamine-metabolizing enzymes, COMT and monoamine oxidase. After 8 wk of ANG II infusion, there were no significant differences in blood pressure between wild-type and COMT KO mice. Compared with wild-type, COMT KO mice had decreased albuminuria and tubulointerstitial injury. In response to ANG II infusion, there was decreased expression of both glomerular and tubulointerstitial injury markers (fibronectin, connective tissue growth factor, fibroblast-specific protein-1, collagen I, podocyte vascular endothelial growth factor) in COMT KO mice. We recently reported that ANG II-mediated tubulointerstitial fibrosis is mediated by src-dependent epidermal growth factor receptor (EGFR) activation. In aromatic l-amino acid decarboxylase knockout (AADC KO) mice, a model of intrarenal dopamine deficiency due to selective proximal tubule AADC deletion, which inhibits intrarenal dopamine synthesis, ANG II infusion further increased expression of p-src and pTyr845-EGFR. In contrast, their expression was markedly attenuated in COMT KO mice. These results demonstrate a role for intrarenal dopamine to buffer the detrimental effects of ANG II upon the kidney.
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Affiliation(s)
- Shilin Yang
- Nashville Veterans Affairs Hospital and Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
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47
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Asghar M, Tayebati SK, Lokhandwala MF, Hussain T. Potential dopamine-1 receptor stimulation in hypertension management. Curr Hypertens Rep 2011; 13:294-302. [PMID: 21633929 DOI: 10.1007/s11906-011-0211-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The role of dopamine receptors in blood pressure regulation is well established. Genetic ablation of both dopamine D1-like receptor subtypes (D1, D5) and D2-like receptor subtypes (D2, D3, D4) results in a hypertensive phenotype in mice. This review focuses on the dopamine D1-like receptor subtypes D1 and D5 (especially D1 receptors), as they play a major role in regulating sodium homeostasis and blood pressure. Studies mostly describing the role of renal dopamine D1-like receptors are included, as the kidneys play a pivotal role in the maintenance of sodium homeostasis and the long-term regulation of blood pressure. We also attempt to describe the interaction between D1-like receptors and other proteins, especially angiotensin II type 1 and type 2 receptors, which are involved in the maintenance of sodium homeostasis and blood pressure. Finally, we discuss a new concept of renal D1 receptor regulation in hypertension that involves oxidative stress mechanisms.
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Affiliation(s)
- Mohammad Asghar
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
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48
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Jin S, Zhou F, Katirai F, Li PL. Lipid raft redox signaling: molecular mechanisms in health and disease. Antioxid Redox Signal 2011; 15:1043-83. [PMID: 21294649 PMCID: PMC3135227 DOI: 10.1089/ars.2010.3619] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial-temporal regulations, and physiological, pathophysiological relevances to human health and diseases.
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Affiliation(s)
- Si Jin
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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49
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Abstract
Dopamine is an important regulator of systemic blood pressure via multiple mechanisms. It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion and water transport and by regulation of hormones and humoral agents. The kidney synthesizes dopamine from circulating or filtered L-DOPA independently from innervation. The major determinants of the renal tubular synthesis/release of dopamine are probably sodium intake and intracellular sodium. Dopamine exerts its actions via two families of cell surface receptors, D1-like receptors comprising D1R and D5R, and D2-like receptors comprising D2R, D3R, and D4R, and by interactions with other G protein-coupled receptors. D1-like receptors are linked to vasodilation, while the effect of D2-like receptors on the vasculature is variable and probably dependent upon the state of nerve activity. Dopamine secreted into the tubular lumen acts mainly via D1-like receptors in an autocrine/paracrine manner to regulate ion transport in the proximal and distal nephron. These effects are mediated mainly by tubular mechanisms and augmented by hemodynamic mechanisms. The natriuretic effect of D1-like receptors is caused by inhibition of ion transport in the apical and basolateral membranes. D2-like receptors participate in the inhibition of ion transport during conditions of euvolemia and moderate volume expansion. Dopamine also controls ion transport and blood pressure by regulating the production of reactive oxygen species and the inflammatory response. Essential hypertension is associated with abnormalities in dopamine production, receptor number, and/or posttranslational modification.
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Affiliation(s)
- Ines Armando
- Children’s National Medical Center—Center for Molecular Physiology Research, Washington, District of Columbia
| | - Van Anthony M. Villar
- Children’s National Medical Center—Center for Molecular Physiology Research, Washington, District of Columbia
| | - Pedro A. Jose
- Children’s National Medical Center—Center for Molecular Physiology Research, Washington, District of Columbia
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50
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Abstract
The assessment of salt sensitivity of blood pressure is difficult because of the lack of universal consensus on definition. Regardless of the variability in the definition of salt sensitivity, increased salt intake, independent of the actual level of blood pressure, is also a risk factor for cardiovascular morbidity and mortality and kidney disease. A modest reduction in salt intake results in an immediate decrease in blood pressure, with long-term beneficial consequences. However, some have suggested that dietary sodium restriction may not be beneficial to everyone. Thus, there is a need to distinguish salt-sensitive from salt-resistant individuals, but it has been difficult to do so with phenotypic studies. Therefore, there is a need to determine the genes that are involved in salt sensitivity. This review focuses on genes associated with salt sensitivity, with emphasis on the variants associated with salt sensitivity in humans that are not due to monogenic causes. Special emphasis is given to gene variants associated with salt sensitivity whose protein products interfere with cell function and increase blood pressure in transgenic mice.
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Affiliation(s)
- Hironobu Sanada
- Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan.
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