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Luo Z, Wu W, Sun Q, Wang J. Accurate and transferable drug-target interaction prediction with DrugLAMP. Bioinformatics 2024; 40:btae693. [PMID: 39570605 PMCID: PMC11629708 DOI: 10.1093/bioinformatics/btae693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/29/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024] Open
Abstract
MOTIVATION Accurate prediction of drug-target interactions (DTIs), especially for novel targets or drugs, is crucial for accelerating drug discovery. Recent advances in pretrained language models (PLMs) and multi-modal learning present new opportunities to enhance DTI prediction by leveraging vast unlabeled molecular data and integrating complementary information from multiple modalities. RESULTS We introduce DrugLAMP (PLM-assisted multi-modal prediction), a PLM-based multi-modal framework for accurate and transferable DTI prediction. DrugLAMP integrates molecular graph and protein sequence features extracted by PLMs and traditional feature extractors. We introduce two novel multi-modal fusion modules: (i) pocket-guided co-attention (PGCA), which uses protein pocket information to guide the attention mechanism on drug features, and (ii) paired multi-modal attention (PMMA), which enables effective cross-modal interactions between drug and protein features. These modules work together to enhance the model's ability to capture complex drug-protein interactions. Moreover, the contrastive compound-protein pre-training (2C2P) module enhances the model's generalization to real-world scenarios by aligning features across modalities and conditions. Comprehensive experiments demonstrate DrugLAMP's state-of-the-art performance on both standard benchmarks and challenging settings simulating real-world drug discovery, where test drugs/targets are unseen during training. Visualizations of attention maps and application to predict cryptic pockets and drug side effects further showcase DrugLAMP's strong interpretability and generalizability. Ablation studies confirm the contributions of the proposed modules. AVAILABILITY AND IMPLEMENTATION Source code and datasets are freely available at https://github.com/Lzcstan/DrugLAMP. All data originate from public sources.
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Affiliation(s)
- Zhengchao Luo
- Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Beijing 100871, China
| | - Wei Wu
- Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Beijing 100871, China
| | - Qichen Sun
- School of Mathematical Sciences, Peking University, Beijing 100871, China
| | - Jinzhuo Wang
- Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Beijing 100871, China
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Zhang F, Armando I, Jose PA, Zeng C, Yang J. G protein-coupled receptor kinases in hypertension: physiology, pathogenesis, and therapeutic targets. Hypertens Res 2024; 47:2317-2336. [PMID: 38961282 PMCID: PMC11374685 DOI: 10.1038/s41440-024-01763-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 05/10/2024] [Accepted: 06/06/2024] [Indexed: 07/05/2024]
Abstract
G protein-coupled receptors (GPCRs) mediate cellular responses to a myriad of hormones and neurotransmitters that play vital roles in the regulation of physiological processes such as blood pressure. In organs such as the artery and kidney, hormones or neurotransmitters, such as angiotensin II (Ang II), dopamine, epinephrine, and norepinephrine exert their functions via their receptors, with the ultimate effect of keeping normal vascular reactivity, normal body sodium, and normal blood pressure. GPCR kinases (GRKs) exert their biological functions, by mediating the regulation of agonist-occupied GPCRs, non-GPCRs, or non-receptor substrates. In particular, increasing number of studies show that aberrant expression and activity of GRKs in the cardiovascular system and kidney inhibit or stimulate GPCRs (e.g., dopamine receptors, Ang II receptors, and α- and β-adrenergic receptors), resulting in hypertension. Current studies focus on the effect of selective GRK inhibitors in cardiovascular diseases, including hypertension. Moreover, genetic studies show that GRK gene variants are associated with essential hypertension, blood pressure response to antihypertensive medicines, and adverse cardiovascular outcomes of antihypertensive treatment. In this review, we present a comprehensive overview of GRK-mediated regulation of blood pressure, role of GRKs in the pathogenesis of hypertension, and highlight potential strategies for the treatment of hypertension. Schematic representation of GPCR desensitization process. Activation of GPCRs begins with the binding of an agonist to its corresponding receptor. Then G proteins activate downstream effectors that are mediated by various signaling pathways. GPCR signaling is halted by GRK-mediated receptor phosphorylation, which causes receptor internalization through β-arrestin.
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Affiliation(s)
- Fuwei Zhang
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
- Department of Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
- Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Ines Armando
- Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology/Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA
| | - Pedro A Jose
- Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology/Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Jian Yang
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
- Department of Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
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Yang D, Tang M, Zhang M, Ren H, Li X, Zhang Z, He B, Peng S, Wang W, Fang D, Song Y, Xiong Y, Liu ZZ, Liang L, Shi W, Fu C, Hu Y, Jose PA, Zhou L, Han Y, Zeng C. Downregulation of G protein-coupled receptor kinase 4 protects against kidney ischemia-reperfusion injury. Kidney Int 2023; 103:719-734. [PMID: 36669643 DOI: 10.1016/j.kint.2022.12.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 10/27/2022] [Accepted: 12/12/2022] [Indexed: 01/19/2023]
Abstract
Ischemia/reperfusion injury of the kidney is associated with high morbidity and mortality, and treatment of this injury remains a challenge. G protein-coupled receptor kinase 4 (GRK4) plays a vital role in essential hypertension and myocardial infarction, but its function in kidney ischemia/reperfusion injury remains undetermined. Among the GRK subtypes (GRK2-6) expressed in kidneys, the increase in GRK4 expression was much more apparent than that of the other four GRKs 24 hours after injury and was found to accumulate in the nuclei of injured mouse and human renal tubule cells. Gain- and loss-of-function experiments revealed that GRK4 overexpression exacerbated acute kidney ischemia/reperfusion injury, whereas kidney tubule-specific knockout of GRK4 decreased injury-induced kidney dysfunction. Necroptosis was the major type of tubule cell death mediated by GRK4, because GRK4 significantly increased receptor interacting kinase (RIPK)1 expression and phosphorylation, subsequently leading to RIPK3 and mixed lineage kinase domain-like protein (MLKL) phosphorylation after kidney ischemia/reperfusion injury, but was reversed by necrostatin-1 pretreatment (an RIPK1 inhibitor). Using co-immunoprecipitation, mass spectrometry, and siRNA screening studies, we identified signal transducer and activator of transcription (STAT)1 as a GRK4 binding protein, which co-localized with GRK4 in the nuclei of renal tubule cells. Additionally, GRK4 phosphorylated STAT1 at serine 727, whose inactive mutation effectively reversed GRK4-mediated RIPK1 activation and tubule cell death. Kidney-targeted GRK4 silencing with nanoparticle delivery considerably ameliorated kidney ischemia/reperfusion injury. Thus, our findings reveal that GRK4 triggers necroptosis and aggravates kidney ischemia/reperfusion injury, and its downregulation may provide a promising therapeutic strategy for kidney protection.
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Affiliation(s)
- Donghai Yang
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Ming Tang
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Mingming Zhang
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Hongmei Ren
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Xiaoping Li
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Ziyue Zhang
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Bo He
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Song Peng
- Department of Urology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China
| | - Wei Wang
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Dandong Fang
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Yi Song
- Department of Cardiac Surgery, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China
| | - Yao Xiong
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China
| | - Zhi Zhao Liu
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China
| | - Lijia Liang
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China
| | - Weibin Shi
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Chunjiang Fu
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Yijie Hu
- Department of Cardiac Surgery, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China
| | - Pedro A Jose
- Division of Renal Diseases & Hypertension, Department of Medicine and Pharmacology-Physiology, The George Washington University School of Medicine & Health Sciences, Washington D.C., USA
| | - Lin Zhou
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China
| | - Yu Han
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China.
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, People's Republic of China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
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Gerhards J, Maerz LD, Matthees ESF, Donow C, Moepps B, Premont RT, Burkhalter MD, Hoffmann C, Philipp M. Kinase Activity Is Not Required for G Protein-Coupled Receptor Kinase 4 Restraining mTOR Signaling during Cilia and Kidney Development. J Am Soc Nephrol 2023; 34:590-606. [PMID: 36810260 PMCID: PMC10103308 DOI: 10.1681/asn.0000000000000082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 11/27/2022] [Indexed: 01/28/2023] Open
Abstract
SIGNIFICANCE STATEMENT G protein-coupled receptor kinase 4 (GRK4) regulates renal sodium and water reabsorption. Although GRK4 variants with elevated kinase activity have been associated with salt-sensitive or essential hypertension, this association has been inconsistent among different study populations. In addition, studies elucidating how GRK4 may modulate cellular signaling are sparse. In an analysis of how GRK4 affects the developing kidney, the authors found that GRK4 modulates mammalian target of rapamycin (mTOR) signaling. Loss of GRK4 in embryonic zebrafish causes kidney dysfunction and glomerular cysts. Moreover, GRK4 depletion in zebrafish and cellular mammalian models results in elongated cilia. Rescue experiments suggest that hypertension in carriers of GRK4 variants may not be explained solely by kinase hyperactivity; instead, elevated mTOR signaling may be the underlying cause. BACKGROUND G protein-coupled receptor kinase 4 (GRK4) is considered a central regulator of blood pressure through phosphorylation of renal dopaminergic receptors and subsequent modulation of sodium excretion. Several nonsynonymous genetic variants of GRK4 have been only partially linked to hypertension, although these variants demonstrate elevated kinase activity. However, some evidence suggests that function of GRK4 variants may involve more than regulation of dopaminergic receptors alone. Little is known about the effects of GRK4 on cellular signaling, and it is also unclear whether or how altered GRK4 function might affect kidney development. METHODS To better understand the effect of GRK4 variants on the functionality of GRK4 and GRK4's actions in cellular signaling during kidney development, we studied zebrafish, human cells, and a murine kidney spheroid model. RESULTS Zebrafish depleted of Grk4 develop impaired glomerular filtration, generalized edema, glomerular cysts, pronephric dilatation, and expansion of kidney cilia. In human fibroblasts and in a kidney spheroid model, GRK4 knockdown produced elongated primary cilia. Reconstitution with human wild-type GRK4 partially rescues these phenotypes. We found that kinase activity is dispensable because kinase-dead GRK4 (altered GRK4 that cannot result in phosphorylation of the targeted protein) prevented cyst formation and restored normal ciliogenesis in all tested models. Hypertension-associated genetic variants of GRK4 fail to rescue any of the observed phenotypes, suggesting a receptor-independent mechanism. Instead, we discovered unrestrained mammalian target of rapamycin signaling as an underlying cause. CONCLUSIONS These findings identify GRK4 as novel regulator of cilia and of kidney development independent of GRK4's kinase function and provide evidence that the GRK4 variants believed to act as hyperactive kinases are dysfunctional for normal ciliogenesis.
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Affiliation(s)
- Julian Gerhards
- Section of Pharmacogenomics, Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Lars D. Maerz
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Edda S. F. Matthees
- Institute for Molecular Cell Biology, University Hospital Jena, Friedrich-Schiller University of Jena, Jena, Germany
| | - Cornelia Donow
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Barbara Moepps
- Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm, Germany
| | - Richard T. Premont
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Martin D. Burkhalter
- Section of Pharmacogenomics, Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Carsten Hoffmann
- Institute for Molecular Cell Biology, University Hospital Jena, Friedrich-Schiller University of Jena, Jena, Germany
| | - Melanie Philipp
- Section of Pharmacogenomics, Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, Germany
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5
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Yang J, Hall JE, Jose PA, Chen K, Zeng C. Comprehensive insights in GRK4 and hypertension: From mechanisms to potential therapeutics. Pharmacol Ther 2022; 239:108194. [PMID: 35487286 PMCID: PMC9728143 DOI: 10.1016/j.pharmthera.2022.108194] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 03/30/2022] [Accepted: 04/21/2022] [Indexed: 11/24/2022]
Abstract
G protein-coupled receptors (GPCRs) mediate cellular responses to diverse extracellular stimuli that play vital roles in the regulation of biology, including behavior. Abnormal G protein-coupled receptor kinase (GRK)-mediated regulation of GPCR function is involved in the pathogenesis of hypertension. Among the seven GRK subtypes, GRK4 has attracted attention because of its constitutive activity and tissue-specific expression. Increasing number of studies show that GRK4 affects blood pressure by GPCR-mediated regulation of renal and arterial function. The target receptor of GRK4 is confined not only to GPCRs, but also to other blood pressure-regulating receptors, such as the adiponectin receptor. Genetic studies in humans show that in several ethnic groups, GRK4 gene variants (R65L, A142V, and A486V) are associated with salt-sensitive or salt-resistant essential hypertension and blood pressure responses to antihypertensive medicines. In this article, we present a comprehensive overview of GRK-mediated regulation of blood pressure, focusing on the latest research progress on GRK4 and hypertension and highlighting potential and novel strategies for the prevention and treatment of hypertension.
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Affiliation(s)
- Jian Yang
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - John E Hall
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Pedro A Jose
- Division of Renal Diseases & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA
| | - Ken Chen
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China.
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Heart Center of Fujian Province, Union Hospital, Fujian Medical University, Fuzhou, PR China; Department of Cardiology, Chongqing General Hospital, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China.
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Grant CE, Flis A, Ryan BM. Understanding the Role of Dopamine in Cancer: Past, Present, and Future. Carcinogenesis 2022; 43:517-527. [PMID: 35616105 DOI: 10.1093/carcin/bgac045] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 05/12/2022] [Accepted: 05/23/2022] [Indexed: 11/14/2022] Open
Abstract
Dopamine (DA, 3-hydroxytyramine) is member of the catecholamine family and is classically characterized according to its role in the central nervous system as a neurotransmitter. In recent decades, many novel and intriguing discoveries have been made about the peripheral expression of DA receptors (DRs) and the role of DA signaling in both normal and pathological processes. Drawing from decades of evidence suggesting a link between DA and cancer, the DA pathway (DAP) has recently emerged as a potential target in antitumor therapies. Due to the onerous, expensive, and frequently unsuccessful nature of drug development, the repurposing of dopaminergic drugs for cancer therapy has the potential to greatly benefit patients and drug developers alike. However, the lack of clear mechanistic data supporting the direct involvement of DRs and their downstream signaling components in cancer represents an ongoing challenge that has limited the translation of these drugs to the clinic. Despite this, the breadth of evidence linking DA to cancer and non-tumor cells in the tumor microenvironment (TME) justifies further inquiry into the potential applications of this treatment modality in cancer. Herein, we review the literature characterizing the interplay between the DA signaling axis and cancer, highlighting key findings, and then propose rational lines of investigation to follow.
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Affiliation(s)
- Christopher E Grant
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Amy Flis
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Bríd M Ryan
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD
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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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Ma C, de Baaij JHF, Millar PJ, Gault VA, de Galan BE, Bindels RJM, Hoenderop JGJ. Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice. Nephron Clin Pract 2019; 142:51-60. [PMID: 30799406 DOI: 10.1159/000496617] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 12/21/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Inhibition of the Na+/glucose co-transporter 2 is a new therapeutic strategy for diabetes. It is unclear how proximal loss of Na+ (and glucose) affects the subsequent Na+ transporters in the proximal tubule (PT), thick ascending limb of loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD). METHODS Mice on a high fat diet were administered 3 doses streptozotocin 6 days prior to oral dapagliflozin administration or vehicle for 18 days. A control group of lean mice were also included. Body weight and glucose were recorded at regular intervals during treatment. Renal Na+ transporters expression in nephron segments were analyzed by RT-qPCR and Western blot. RESULTS Dapagliflozin treatment resulted in a significant reduction in body weight and blood glucose compared to vehicle-treated controls. mRNA results showed that Na+-hydrogen antiporter 3 (NHE3), Na+/phosphate cotransporter (NaPi-2a) and epithelial Na+ channel expression was increased, Ncx1, ENaCβ and ENaCγ expression declined (p all < 0.05), respectively, in dapagliflozin-treated mice when compared with saline vehicle mice. Na-K-2Cl cotransporters and Na-Cl cotransporter mRNA expression was not affected by dapagliflozin treatment. Na+/K+-ATPase (Atp1b1) expression was also increased significantly by dapagliflozin treatment, but it did not affect Atp1a1 and glucose transporter 2 expression. Western blot analysis showed that NaPi-2a, NHE3 and ATP1b1 expression was upregulated in dapagliflozin-treated diabetic mice when compared with saline vehicle mice (p < 0.05). CONCLUSION Our findings suggest that dapagliflozin treatment augments compensatory changes in the renal PT in diabetic mice.
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Affiliation(s)
- Chao Ma
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Paul J Millar
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
| | - Victor A Gault
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
| | - Bastiaan E de Galan
- Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - René J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands,
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9
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Tiu AC, Bishop MD, Asico LD, Jose PA, Villar VAM. Primary Pediatric Hypertension: Current Understanding and Emerging Concepts. Curr Hypertens Rep 2017; 19:70. [PMID: 28780627 PMCID: PMC6314210 DOI: 10.1007/s11906-017-0768-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.
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Affiliation(s)
- Andrew C Tiu
- Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, 2300 I Street, N.W. Washington, DC, 20037, USA.
| | - Michael D Bishop
- Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, 2300 I Street, N.W. Washington, DC, 20037, USA
| | - Laureano D Asico
- Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, 2300 I Street, N.W. Washington, DC, 20037, USA
| | - Pedro A Jose
- Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, 2300 I Street, N.W. Washington, DC, 20037, USA
| | - Van Anthony M Villar
- Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, 2300 I Street, N.W. Washington, DC, 20037, USA
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Iatrino R, Manunta P, Zagato L. Salt Sensitivity: Challenging and Controversial Phenotype of Primary Hypertension. Curr Hypertens Rep 2016; 18:70. [DOI: 10.1007/s11906-016-0677-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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11
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Yang J, Villar VAM, Armando I, Jose PA, Zeng C. G Protein-Coupled Receptor Kinases: Crucial Regulators of Blood Pressure. J Am Heart Assoc 2016; 5:JAHA.116.003519. [PMID: 27390269 PMCID: PMC5015388 DOI: 10.1161/jaha.116.003519] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Jian Yang
- Department of Nutrition, Daping Hospital, The Third Military Medical University, Chongqing, China Department of Cardiology, Chongqing Key Laboratory for Hypertension, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Van Anthony M Villar
- Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Ines Armando
- Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Pedro A Jose
- Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Chunyu Zeng
- Department of Cardiology, Chongqing Key Laboratory for Hypertension, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, Chongqing, China
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12
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Cwynar M, Gąsowski J, Głuszewska A, Królczyk J, Bartoń H, Słowik A, Grodzicki T. Blood pressure, arterial stiffness and endogenous lithium clearance in relation to AGTR1 A1166C and AGTR2 G1675A gene polymorphisms. J Renin Angiotensin Aldosterone Syst 2016; 17:1470320316655669. [PMID: 27339867 PMCID: PMC5843941 DOI: 10.1177/1470320316655669] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 05/17/2016] [Indexed: 01/18/2023] Open
Abstract
Introduction: Although recently a matter of epidemiologic controversy, sodium overload and its interaction with genetic factors predispose to hypertension and related target organ complications. Methods: In 131 (66 male) treated hypertensives, we measured peripheral and central arterial pressures and pulse wave augmentation indexes (AIxP, AIxC1, AIxC2), pulse wave velocity (PWV), daily urinary sodium excretion and did genetic studies of AGTR1 A1166C and AGTR2 G1675A polymorphisms. Proximal (FELi) and distal (FDRNa) sodium reabsorption measurements were performed using endogenous lithium clearance. Results: In men, we found interaction between FDRNa and AGTR2 G1675A polymorphism with respect to AIxC1 (pINT=0.01), AIxC2 (pINT=0.05) and AIxP (pINT=0.006). Arterial stiffness increased with higher sodium reabsorption in the distal tubule, in the presence of AGTR2 G allele with the opposite tendency in A allele carriers. In the subgroup with FDRNa below median, as compared to those with FDRNa above median, the AIxC1 (139.6±3.8 vs 159.1±5.7%; p=0.009), AIxC2 (26.3±1.8 vs 33.3±1.7%; p=0.016) and AIxP (83.4±2.5 vs 96.5±2.6%; p<0.0001) were lower, in the G allele carrying men and GG homozygous women. Conclusions: The relation between sodium reabsorption in the distal tubule and the development of arterial stiffness depends on the AGTR2 G1675A polymorphism in blood pressure independent fashion.
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Affiliation(s)
- Marcin Cwynar
- Department of Internal Medicine and Gerontology, Jagiellonian University, Poland
| | - Jerzy Gąsowski
- Department of Internal Medicine and Gerontology, Jagiellonian University, Poland
| | - Anna Głuszewska
- Department of Internal Medicine and Gerontology, Jagiellonian University, Poland
| | - Jarosław Królczyk
- Department of Internal Medicine and Gerontology, Jagiellonian University, Poland
| | - Henryk Bartoń
- Department of Food Chemistry and Nutrition, Jagiellonian University, Poland
| | | | - Tomasz Grodzicki
- Department of Internal Medicine and Gerontology, Jagiellonian University, Poland
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13
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Affiliation(s)
- Pedro A Jose
- From the Departments of Medicine and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC (P.A.J.); Department of Pathology, The University of Virginia, Charlottesville (R.A.F.); Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Centre, Peking Union Medical College, Beijing, P.R. China (Z.Y.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, P.R. China (C.Z.); and Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.).
| | - Robin A Felder
- From the Departments of Medicine and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC (P.A.J.); Department of Pathology, The University of Virginia, Charlottesville (R.A.F.); Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Centre, Peking Union Medical College, Beijing, P.R. China (Z.Y.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, P.R. China (C.Z.); and Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.)
| | - Zhiwei Yang
- From the Departments of Medicine and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC (P.A.J.); Department of Pathology, The University of Virginia, Charlottesville (R.A.F.); Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Centre, Peking Union Medical College, Beijing, P.R. China (Z.Y.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, P.R. China (C.Z.); and Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.)
| | - Chunyu Zeng
- From the Departments of Medicine and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC (P.A.J.); Department of Pathology, The University of Virginia, Charlottesville (R.A.F.); Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Centre, Peking Union Medical College, Beijing, P.R. China (Z.Y.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, P.R. China (C.Z.); and Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.)
| | - Gilbert M Eisner
- From the Departments of Medicine and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC (P.A.J.); Department of Pathology, The University of Virginia, Charlottesville (R.A.F.); Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Centre, Peking Union Medical College, Beijing, P.R. China (Z.Y.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, P.R. China (C.Z.); and Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.)
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Abstract
PURPOSE OF REVIEW Hypertension, which is present in about one quarter of the world's population, is responsible for about 41% of the number one cause of death - cardiovascular disease. Not included in these statistics is the effect of sodium intake on blood pressure, even though an increase or a marked decrease in sodium intake can increase blood pressure. This review deals with the interaction of gut microbiota and the kidney with genetics and epigenetics in the regulation of blood pressure and salt sensitivity. RECENT FINDINGS The abundance of the gut microbes, Firmicutes and Bacteroidetes, is associated with increased blood pressure in several models of hypertension, including the spontaneously hypertensive and Dahl salt-sensitive rats. Decreasing gut microbiota by antibiotics can increase or decrease blood pressure that is influenced by genotype. The biological function of probiotics may also be a consequence of epigenetic modification, related, in part, to microRNA. Products of the fermentation of nutrients by gut microbiota can influence blood pressure by regulating expenditure of energy, intestinal metabolism of catecholamines, and gastrointestinal and renal ion transport, and thus, salt sensitivity. SUMMARY The beneficial or deleterious effect of gut microbiota on blood pressure is a consequence of several variables, including genetics, epigenetics, lifestyle, and intake of antibiotics. These variables may influence the ultimate level of blood pressure and control of hypertension.
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15
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Orun O. Roles of catecholamine related polymorphisms in hypertension. World J Hypertens 2016; 6:41-52. [DOI: 10.5494/wjh.v6.i1.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/19/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023] Open
Abstract
The objective of this review is to summarize current data obtained so far in catecholamine-essential hypertension (EH) relationships on a genetic basis. As the major elements driving the sympathetic system’s actions, catecholamines modulate a variety of physiological processes and mutations related to the system. This could generate serious disorders, such as severe mental illnesses, stress-induced disorders, or impaired control of blood pressure or motor pathways. EH is idiopathic, and the genetic basis of its causes and substantial interindividual discrepancies in response to different types of treatments are the focus of interest. Susceptibility to disease or efficacy of treatments are thought to reflect genomic variabilities among individuals. Therefore, outlining the available knowledge in functional genetic polymorphisms linked to EH will make the picture clearer and will help to establish future prospects in the field.
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16
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Cwynar M, Gąsowski J, Gryglewska B, Głuszewska A, Bartoń H, Słowik A, Grodzicki T. The relation between ACE D/I and CYP11B2 C-344T polymorphisms and parameters of arterial stiffness in the context of renal sodium handling. Blood Press 2015. [DOI: 10.3109/08037051.2015.1070476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Marcin Cwynar
- Department of Internal Medicine and Gerontology, Krakow, Poland
| | - Jerzy Gąsowski
- Department of Internal Medicine and Gerontology, Krakow, Poland
| | | | - Anna Głuszewska
- Department of Internal Medicine and Gerontology, Krakow, Poland
| | - Henryk Bartoń
- Trace Element Research Laboratory, Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Krakow, Poland
| | - Agnieszka Słowik
- Department of Neurology, Medical College, Jagiellonian University, Krakow, Poland
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Yang J, Villar VAM, Jones JE, Jose PA, Zeng C. G protein-coupled receptor kinase 4: role in hypertension. Hypertension 2015; 65:1148-55. [PMID: 25870190 DOI: 10.1161/hypertensionaha.115.05189] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 03/22/2015] [Indexed: 12/15/2022]
Affiliation(s)
- Jian Yang
- From the Departments of Cardiology (J.Y., C.Z.) and Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China; and Division of Nephrology, Department of Medicine (V.A.M.V., J.E.J., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore
| | - Van Anthony M Villar
- From the Departments of Cardiology (J.Y., C.Z.) and Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China; and Division of Nephrology, Department of Medicine (V.A.M.V., J.E.J., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore
| | - John E Jones
- From the Departments of Cardiology (J.Y., C.Z.) and Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China; and Division of Nephrology, Department of Medicine (V.A.M.V., J.E.J., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore
| | - Pedro A Jose
- From the Departments of Cardiology (J.Y., C.Z.) and Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China; and Division of Nephrology, Department of Medicine (V.A.M.V., J.E.J., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore
| | - Chunyu Zeng
- From the Departments of Cardiology (J.Y., C.Z.) and Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China; and Division of Nephrology, Department of Medicine (V.A.M.V., J.E.J., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
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18
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Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. THE PHARMACOGENOMICS JOURNAL 2015; 16:3-9. [PMID: 25732908 DOI: 10.1038/tpj.2015.6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 12/19/2014] [Indexed: 12/13/2022]
Abstract
Non-synonymous GRK4 variants, R65L, A142V and A486V, are associated with essential hypertension in diverse populations. This study replicated the association of GRK4 variants, including GRK4(142V), with human essential hypertension in a Japanese population (n=588; hypertensive, n=486 normotensive controls) and determined whether the presence of GRK4 variants predicted the blood pressure (BP) response to angiotensin receptor blockers (ARBs) in patients with essential hypertension. We analyzed 829 patients and compared the response to ARBs between individuals with no GRK4 variants (n=136) and those with variants at one or any of the three loci (n=693). Carriers of hGRK4(142V) had a greater decrease in systolic BP in response to ARBs than non-carrier hypertensive patients. By contrast, those with variants only at GRK4(486V) were less likely to achieve the BP goal in response to an ARB than those with no variants. These studies showed for the first time the association between GRK4(142V) and a larger decrease in BP with ARBs in hypertensive patients.
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19
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Blood pressure and arterial stiffness in patients with high sodium intake in relation to sodium handling and left ventricular diastolic dysfunction status. J Hum Hypertens 2015; 29:583-91. [DOI: 10.1038/jhh.2015.1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 11/14/2014] [Accepted: 11/24/2014] [Indexed: 11/09/2022]
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20
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Citterio L, Ferrandi M, Delli Carpini S, Simonini M, Kuznetsova T, Molinari I, Dell' Antonio G, Lanzani C, Merlino L, Brioni E, Staessen JA, Bianchi G, Manunta P. cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment. Hypertension 2013; 62:1027-33. [PMID: 24060892 DOI: 10.1161/hypertensionaha.113.01628] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Defective pressure-natriuresis related to abnormalities in the natriuretic response has been associated with hypertension development. A major signaling pathway mediating pressure natriuresis involves the cGMP-dependent protein kinase 1 (PRKG1) that, once activated by Src kinase, inhibits renal Na(+) reabsorption via a direct action on basolateral Na-K ATPase and luminal Na-H exchanger type 3, as shown in renal tubuli of animals. Because a clear implication of PRKG1 in humans is still lacking, here we addressed whether PRKG1 polymorphisms affect pressure-natriuresis in patients. Naive hypertensive patients (n = 574), genotyped for PRKG1 rs1904694, rs7897633, and rs7905063 single nucleotide polymorphisms (SNPs), underwent an acute Na(+) loading, and the slope of the pressure-natriuresis relationship between blood pressure and Na(+) excretion was calculated. The underlying molecular mechanism was investigated by immunoblotting protein quantifications in human kidneys. The results demonstrate that the PRKG1 risk haplotype GAT (rs1904694, rs7897633, rs7905063, respectively) associates with a rightward shift of the pressure-natriuresis curve (0.017 ± 0.004 μEq/mm Hg per minute) compared with the ACC (0.0013 ± 0.003 μEq/mm Hg per minute; P = 0.001). In human kidneys, a positive correlation of protein expression levels between PRKG1 and Src (r = 0.83; P<0.001) or α1 Na-K ATPase (r = 0.557; P<0.01) and between α1 Na-K ATPase and Na-H exchanger type 3 (r = 0.584; P<0.01) or Src (r = 0.691; P<0.001) was observed in patients carrying PRKG1 risk GAT (n = 23) but not ACC (n = 14) variants. A functional signaling complex among PRKG1, α1 Na-K ATPase, and Src was shown by immunoprecipitation from human renal caveolae. These findings indicate that PRKG1 risk alleles associate with salt-sensitivity related to a loss of the inhibitory control of renal Na(+) reabsorption, suggestive of a blunt pressure-natriuresis response.
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Affiliation(s)
- Lorena Citterio
- San Raffaele Scientific Institute, Nephrology and Dialysis, Università Vita Salute San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
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22
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Genetic variation in CYP17A1 is associated with arterial stiffness in diabetic subjects. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:827172. [PMID: 23133444 PMCID: PMC3485973 DOI: 10.1155/2012/827172] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 09/24/2012] [Accepted: 09/24/2012] [Indexed: 12/12/2022]
Abstract
Hypertension and arterial stiffness are associated with an increasing risk of diabetes and cardiovascular diseases. This study aimed to identify genetic variants affecting hypertension and arterial stiffness in diabetic subjects and to compare genetic associations with hypertension between prediabetic and diabetic subjects. A total of 1,069 participants (326 prediabetic and 743 diabetic subjects) were assessed to determine the genetic variants affecting hypertension by analyzing 52 SNPs previously reported to be associated with hypertension. Moreover, the SNPs were tested for association with hemodynamic parameters related to hypertension. Out of the 52 SNPs analyzed, four SNPs including rs5326 (DRD1), rs1004467 (CYP17A1), rs2960306 (GRK4), and rs11191548 (near NT5C2) in diabetic subjects and rs1530440 (C10orf107) in prediabetic subjects showed a modest association with hypertension (P = 0.0265, 0.0020, 0.0066, 0.0078, and 0.0015, resp; all were insignificant after Bonferroni correction). Of these SNPs, rs1004467 in CYP17A1 was significantly associated with augmentation index in diabetic subjects who were not taking antihypertensive medication (P = 0.0001; corrected P = 0.006) but not in diabetic subjects receiving antihypertensive medication. This finding suggests that certain genetic variations found in diabetic subjects may confer arterial stiffness and the development of hypertension and also be affected by antihypertensive medication.
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Vandell AG, Lobmeyer MT, Gawronski BE, Langaee TY, Gong Y, Gums JG, Beitelshees AL, Turner ST, Chapman AB, Cooper-DeHoff RM, Bailey KR, Boerwinkle E, Pepine CJ, Liggett SB, Johnson JA. G protein receptor kinase 4 polymorphisms: β-blocker pharmacogenetics and treatment-related outcomes in hypertension. Hypertension 2012; 60:957-64. [PMID: 22949529 DOI: 10.1161/hypertensionaha.112.198721] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (-9.1±6.8 versus -6.8±7.1 versus -5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P=0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48-3.55]; P=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.
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Affiliation(s)
- Alexander G Vandell
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida College of Pharmacy, 1600 SW Archer Rd, Room PG-22, Box 100486, Gainesville, FL 32610-0486, USA
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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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Between candidate genes and whole genomes: time for alternative approaches in blood pressure genetics. Curr Hypertens Rep 2012; 14:46-61. [PMID: 22161147 DOI: 10.1007/s11906-011-0241-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.
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Abstract
PURPOSE OF REVIEW This review will highlight the recent findings concerning the role of the intrarenal dopaminergic system in hypertension, especially the role of alterations in G-protein receptor kinase 4 (GRK4) activity. RECENT FINDINGS Recent studies highlight the importance of the intrarenal dopaminergic system in blood pressure regulation and how defects in dopamine signaling are involved in the development of hypertension. There are recent experimental models that definitively demonstrate that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. Furthermore, studies in experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation because of receptor desensitization resulting from increased GRK4 activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II AT1 receptor activity and are associated with essential hypertension in a number of different human cohorts. SUMMARY The ongoing elucidation of this important regulatory pathway further emphasizes the importance of the kidney in maintenance of blood pressure control and may help to delineate the underlying mechanisms predisposing individuals or populations to increased risk for development of hypertension.
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27
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Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis. THE PHARMACOGENOMICS JOURNAL 2012; 13:218-26. [PMID: 22310353 DOI: 10.1038/tpj.2012.1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.
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Lymperopoulos A, Bathgate A. Pharmacogenomics of the heptahelical receptor regulators G-protein-coupled receptor kinases and arrestins: the known and the unknown. Pharmacogenomics 2012; 13:323-341. [PMID: 22304582 DOI: 10.2217/pgs.11.178] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Heptahelical G-protein-coupled receptors are the most diverse and therapeutically important family of receptors, playing major roles in the physiology of various organs and tissues. They couple their ligand binding to G-protein activation, which then transmits intracellular signals. G-protein signaling is terminated by phosphorylation of the receptor by the family of G-protein-coupled receptor kinases (GRKs), followed by arrestin (Arr) binding, which uncouples the phosphorylated receptor from the G-protein and subsequently targets the receptor for internalization. Moreover, Arrs can transmit signals in their own right during receptor internalization. Genetic polymorphisms in receptors, as well as in GRK and Arr family members per se, which affect regulation of receptor signaling and function, have just started being identified and characterized. The present review will discuss what is known so far in this evolving field of GRK/Arr pharmacogenomics, as well as highlight important areas likely to produce invaluable information in the future.
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Affiliation(s)
- Anastasios Lymperopoulos
- Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328, USA.
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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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Odili AN, Richart T, Thijs L, Kingue S, Boombhi HJ, Lemogoum D, Kaptue J, Kamdem MK, Mipinda JB, Omotoso BA, Kolo PM, Aderibigbe A, Ulasi II, Anisiuba BC, Ijoma CK, Ba SA, Ndiaye MB, Staessen JA, M'buyamba-Kabangu JR. Rationale and design of the Newer Versus Older Antihypertensive Agents in African Hypertensive Patients (NOAAH) trial. Blood Press 2011; 20:256-66. [PMID: 21495829 DOI: 10.3109/08037051.2011.572614] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Sub-Saharan Africa experiences an epidemic surge in hypertension. Studies in African Americans led to the recommendation to initiate antihypertensive treatment in Blacks with a diuretic or a low-dose fixed combination including a diuretic. We mounted the Newer versus Older Antihypertensive Agents in African Hypertensive Patients (NOAAH) trial to compare in native African patients a fixed combination of newer drugs, not involving a diuretic, with a combination of older drugs including a diuretic. METHODS Patients aged 30-69 years with uncomplicated hypertension (140-179/90-109 mmHg) and two or fewer associated risk factors are eligible. After a 4-week run-in period off treatment, 180 patients will be randomized to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg or amlodipine/valsartan 5/160 mg. To attain and maintain blood pressure below 140/90 mmHg during 6 months of follow-up, the doses of bisoprolol and amlodipine in the combination tablets will be increased to 10 mg/day with the possible addition of α-methyldopa or hydralazine. NOAAH is powered to demonstrate a 5-mmHg between-group difference in sitting systolic pressure with a two-sided p-value of 0.01 and 90% power. NOAAH is investigator-led and complies with the Helsinki declaration. RESULTS Six centers in four sub-Saharan countries started patient recruitment on September 1, 2010. On December 1, 195 patients were screened, 171 were enrolled, and 51 were randomized and followed up. The trial will be completed in the third quarter of 2011. CONCLUSIONS NOAAH (NCT01030458) is the first randomized multicenter trial of antihypertensive medications in hypertensive patients born and living in sub-Saharan Africa.
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Affiliation(s)
- Augustine N Odili
- Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium
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Orun O, Nacar C, Cabadak H, Tiber PM, Doğan Y, Güneysel Ö, Fak AS, Kan B. Investigation of the association between dopamine D1 receptor gene polymorphisms and essential hypertension in a group of Turkish subjects. Clin Exp Hypertens 2011; 33:418-21. [PMID: 21797797 DOI: 10.3109/10641963.2011.561898] [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
Dopamine has been shown to influence blood pressure by regulating renal sodium excretion through direct interaction with the dopamine receptors, especially with the Dopamine D1 receptor (DRD1). To better understand the role of polymorphisms in those effects, we investigated the association between two polymorphic sites in the DRD1 promoter region (A-48G, G-94A) and essential hypertension in the Turkish population. The DRD1 variants were genotyped by restriction fragment length polymorphism (RFLP) analysis. A total of 205 unrelated individuals were enrolled in the study. We found that genotype distributions and allele frequencies of the control and hypertensive subjects were very similar and did not show any significant difference with respect to blood pressure (BP) and hypertension. Contribution of the gene variances in BP or hypertension by sex differences and dependence on body mass index (BMI) were also evaluated. Distribution of genotypes and allele frequencies were found to be in line with previous reports. However, increments detected in hypertensive subjects were far from being statistically significant.
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Affiliation(s)
- Oya Orun
- Marmara University School of Medicine, Department of Biophysics, Istanbul, Turkey.
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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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Abstract
Clinical trials have demonstrated that a reduced intake of dietary sodium lowers blood pressure. However, blood pressure reduction in response to a decrease in dietary sodium intake varies considerably among different individuals-a phenomenon described as sodium sensitivity. The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study was a large family-based dietary-feeding study conducted in rural north China. This study indicated that approximately 39% of Chinese adults were sodium-sensitive. Sodium sensitivity was more common in women and in persons who were older and had higher usual blood pressure. Sodium sensitivity was also more common in individuals with higher responses to a cold pressor test and in individuals with the metabolic syndrome. Genetic factors may play an important role in determining sodium sensitivity in the Chinese population. A better understanding of the genetic and environmental determinants of sodium sensitivity has important public health and clinical implications.
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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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Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011; 63:182-217. [PMID: 21303898 DOI: 10.1124/pr.110.002642] [Citation(s) in RCA: 1890] [Impact Index Per Article: 135.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.
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Affiliation(s)
- Jean-Martin Beaulieu
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval–Centre de Recherche de l'Université Laval Robert-Giffard, Québec-City, Québec, Canada
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Rhee MY, Yang SJ, Oh SW, Park Y, Kim CI, Park HK, Park SW, Park CY. Novel genetic variations associated with salt sensitivity in the Korean population. Hypertens Res 2011; 34:606-11. [DOI: 10.1038/hr.2010.278] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Dorn GW. Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol Rev 2010; 90:1013-62. [PMID: 20664078 DOI: 10.1152/physrev.00001.2010] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
This review examines the impact of recent discoveries defining personal genetics of adrenergic signaling polymorphisms on scientific discovery and medical practice related to cardiovascular diseases. The adrenergic system is the major regulator of minute-by-minute cardiovascular function. Inhibition of adrenergic signaling with pharmacological beta-adrenergic receptor antagonists (beta-blockers) is first-line therapy for heart failure and hypertension. Advances in pharmacology, molecular biology, and genetics of adrenergic signaling pathways have brought us to the point where personal genetic differences in adrenergic signaling factors are being assessed as determinants of risk or progression of cardiovascular disease. For a few polymorphisms, functional data generated in cell-based systems, genetic mouse models, and pharmacological provocation of human subjects are concordant with population studies that suggest altered risk of cardiovascular disease or therapeutic response to beta-blockers. For the majority of adrenergic pathway polymorphisms however, published data conflict, and the clinical relevance of individual genotyping remains uncertain. Here, the current state of laboratory and clinical evidence that adrenergic pathway polymorphisms can affect cardiovascular pathophysiology is comprehensively reviewed and compared, with a goal of placing these data in the broad context of potential clinical applicability.
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Affiliation(s)
- Gerald W Dorn
- Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Gildea JJ, Shah I, Weiss R, Casscells ND, McGrath HE, Zhang J, Jones JE, Felder RA. HK-2 human renal proximal tubule cells as a model for G protein-coupled receptor kinase type 4-mediated dopamine 1 receptor uncoupling. Hypertension 2010; 56:505-11. [PMID: 20660820 DOI: 10.1161/hypertensionaha.110.152256] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
HK-2 human renal proximal tubule cells (RPTC) are commonly used in the in vitro study of "normal" RPTCs. We discovered recently that HK-2 cells are uncoupled from dopamine 1 receptor (D(1)R) adenylyl cyclase (AC) stimulation. We hypothesized that G protein-coupled receptor kinase type 4 (GRK4) single nucleotide polymorphisms may be responsible for the D(1)R/AC uncoupling in HK-2. This hypothesis was tested by genotyping GRK4 single nucleotide polymorphisms, measuring D(1)-like receptor agonist (fenoldopam)-stimulated cAMP accumulation, quantifying D(1)R inhibition of sodium transport, and testing the ability of GRK4 small interfering RNA to reverse the D(1)R/AC uncoupling. We compared HK-2 with 2 normally coupled human RPTC cell lines and 2 uncoupled RPTC cell lines. The HK-2 cell line was found to have 4 of 6 potential GRK4 single nucleotide polymorphisms known to uncouple the D(1)R from AC (namely, R65L, A142V, and A486V). AC response to fenoldopam stimulation was increased in the 2 normally coupled human RPTC cell lines (FEN: 2.02+/-0.05-fold and 2.33+/-0.19-fold over control; P<0.001; n=4) but not in the 2 uncoupled or HK-2 cell lines. GRK4 small interfering RNA rescued the fenoldopam-mediated AC stimulation in the uncoupled cells, including HK-2. The expected fenoldopam-mediated inhibition of sodium hydrogen exchanger type 3 was absent in HK-2 (n=6) and uncoupled RPTC cell lines (n=6) but was observed in the 2 normally coupled human RPTC cell lines (-25.41+/-4.7% and -27.36+/-2.70%; P<0.001; n=6), which express wild-type GRK4. Despite the fact that HK-2 cells retain many functional characteristics of RPTCs, they are not normal from the perspective of dopaminergic function.
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Affiliation(s)
- John J Gildea
- University of Virginia, PO Box 801400, Charlottesville, VA 22908, USA
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Renal function and genetic variation in dopamine D(1) receptor: is the case strong enough? Kidney Int 2010; 76:1019-22. [PMID: 19876054 DOI: 10.1038/ki.2009.328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Polymorphisms in the genes involved in the dopaminergic system have been implicated in susceptibility to hypertension. A new study by Fung et al. takes a closer look at the association of genetic variants in the dopamine D(1) receptor gene (DRD1) with blood pressure and renal parameters. Although the study does not confirm an association with blood pressure, it suggests a new link between a common variant in the 5'-untranslated region of the DRD1 gene and low glomerular filtration rate.
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Jose PA, Soares-da-Silva P, Eisner GM, Felder RA. Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation. Biochim Biophys Acta Mol Basis Dis 2010; 1802:1259-67. [PMID: 20153824 DOI: 10.1016/j.bbadis.2010.02.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2009] [Revised: 02/05/2010] [Accepted: 02/07/2010] [Indexed: 12/11/2022]
Abstract
Complex interactions between genes and environment result in a sodium-induced elevation in blood pressure (salt sensitivity) and/or hypertension that lead to significant morbidity and mortality affecting up to 25% of the middle-aged adult population worldwide. Determining the etiology of genetic and/or environmentally-induced high blood pressure has been difficult because of the many interacting systems involved. Two main pathways have been implicated as principal determinants of blood pressure since they are located in the kidney (the key organ responsible for blood pressure regulation), and have profound effects on sodium balance: the dopaminergic and renin-angiotensin systems. These systems counteract or modulate each other, in concert with a host of intracellular second messenger pathways to regulate sodium and water balance. In particular, the G protein-coupled receptor kinase type 4 (GRK4) appears to play a key role in regulating dopaminergic-mediated natriuresis. Constitutively activated GRK4 gene variants (R65L, A142V, and A486V), by themselves or by their interaction with other genes involved in blood pressure regulation, are associated with essential hypertension and/or salt-sensitive hypertension in several ethnic groups. GRK4γ 142Vtransgenic mice are hypertensive on normal salt intake while GRK4γ 486V transgenic mice develop hypertension only with an increase in salt intake. GRK4 gene variants have been shown to hyperphosphorylate, desensitize, and internalize two members of the dopamine receptor family, the D(1) (D(1)R) and D(3) (D(3)R) dopamine receptors, but also increase the expression of a key receptor of the renin-angiotensin system, the angiotensin type 1 receptor (AT(1)R). Knowledge of the numerous blood pressure regulatory pathways involving angiotensin and dopamine may provide new therapeutic approaches to the pharmacological regulation of sodium excretion and ultimately blood pressure control.
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Affiliation(s)
- Pedro A Jose
- Children's National Medical Center, George Washington University for the Health Sciences, Washington, DC, USA.
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Escano CS, Armando I, Wang X, Asico LD, Pascua A, Yang Y, Wang Z, Lau YS, Jose PA. Renal dopaminergic defect in C57Bl/6J mice. Am J Physiol Regul Integr Comp Physiol 2009; 297:R1660-9. [PMID: 19726707 DOI: 10.1152/ajpregu.00147.2009] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The C57Bl/6J mouse strain, the genetic background of many transgenic and gene knockout models, is salt sensitive and resistant to renal injury. We tested the hypothesis that renal dopaminergic function is defective in C57Bl/6J mice. On normal NaCl (0.8%, 1 wk) diet, anesthetized and conscious (telemetry) blood pressures were similar in C57Bl/6J and SJL/J mice. High NaCl (6%, 1 wk) increased blood pressure (approximately 30%) in C57Bl/6J but not in SJL/J mice and urinary dopamine to greater extent in SJL/J than in C57Bl/6J mice. Absolute and fractional sodium excretions were lower in SJL/J than in C57Bl/6J mice. The blood pressure-natriuresis plot was shifted to the right in C57Bl/6J mice. Renal expressions of D(1)-like (D(1)R and D(5)R) and angiotensin II AT(1) receptors were similar on normal salt, but high salt increased D(5)R only in C57Bl/6J. GRK4 expression was lower on normal but higher on high salt in C57Bl/6J than in SJL/J mice. Salt increased the excretion of microalbumin and 8-isoprostane (oxidative stress marker) and the degree of renal injury to a greater extent in SJL/J than in C57Bl/6J mice. A D(1)-like receptor agonist increased sodium excretion whereas a D(1)-like receptor antagonist decreased sodium excretion in SJL/J but not in C57Bl/6J mice. In contrast, parathyroid hormone had a similar natriuretic effect in both strains. These results show that defective D(1)-like receptor function is a major cause of salt sensitivity in C57Bl/6J mice, decreased renal dopamine production might also contribute. The relative resistance to renal injury of C57Bl/6J may be a consequence of decreased production of reactive oxygen species.
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Affiliation(s)
- Crisanto S Escano
- Children's National Medical Center, Center for Molecular Physiology Research, Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, USA
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Jin Y, Kuznetsova T, Maillard M, Richart T, Thijs L, Bochud M, Herregods MC, Burnier M, Fagard R, Staessen JA. Independent Relations of Left Ventricular Structure With the 24-Hour Urinary Excretion of Sodium and Aldosterone. Hypertension 2009; 54:489-95. [DOI: 10.1161/hypertensionaha.109.130492] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Yu Jin
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Tatiana Kuznetsova
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Marc Maillard
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Tom Richart
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Lutgarde Thijs
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Murielle Bochud
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Marie-Christine Herregods
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Michel Burnier
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Robert Fagard
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
| | - Jan A. Staessen
- From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.J., T.K., T.R., L.T., R.F., J.A.S.), and the Division of Cardiology, Department of Cardiovascular Diseases (M.C.H.), University of Leuven, Belgium; the Department of Epidemiology (T.R., J.A.S.), Maastricht University, the Netherlands; and the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland
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Wang X, Armando I, Upadhyay K, Pascua A, Jose PA. The regulation of proximal tubular salt transport in hypertension: an update. Curr Opin Nephrol Hypertens 2009; 18:412-420. [PMID: 19654544 PMCID: PMC3722593 DOI: 10.1097/mnh.0b013e32832f5775] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Renal proximal tubular sodium reabsorption is regulated by sodium transporters, including the sodium glucose transporter, sodium amino acid transporter, sodium hydrogen exchanger isoform 3 and sodium phosphate cotransporter type 2 located at the luminal/apical membrane, and sodium bicarbonate cotransporter and Na+/K+ATPase located at the basolateral membrane. This review summarizes recent studies on sodium transporters that play a major role in the increase in blood pressure in essential/polygenic hypertension. RECENT FINDINGS Sodium transporters and Na+/K+ATPase are segregated in membrane lipid and nonlipid raft microdomains that regulate their activities and trafficking via cytoskeletal proteins. The increase in renal proximal tubule ion transport in polygenic hypertension is primarily due to increased activity of NHE3 and Cl/HCO3 exchanger at the luminal/apical membrane and a primary or secondary increase in Na+/K+ATPase activity. SUMMARY The increase in renal proximal tubule ion transport in hypertension is due to increased actions by prohypertensive factors that are unopposed by antihypertensive factors.
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Affiliation(s)
- Xiaoyan Wang
- Center for Molecular Physiology Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
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Fung MM, Rana BK, Tang CM, Shiina T, Nievergelt CM, Rao F, Salem RM, Waalen J, Ziegler MG, Insel PA, O'Connor DT. Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits. Kidney Int 2009; 76:1070-80. [PMID: 19675531 DOI: 10.1038/ki.2009.306] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5'-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.
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Affiliation(s)
- Maple M Fung
- Department of Medicine, Veterans Affairs San Diego Healthcare System and University of California at San Diego, La Jolla, California 92093-0838, USA
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Mayan H, Melnikov S, Novikov I, Holtzman EJ, Farfel Z. Familial hyperkalemia and hypertension: pathogenetic insights based on lithium clearance. J Clin Endocrinol Metab 2009; 94:3010-6. [PMID: 19491230 DOI: 10.1210/jc.2008-2572] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
CONTEXT Familial hyperkalemia and hypertension (FHHt) is caused by mutations in WNK kinases. Its pathogenesis is not completely understood. OBJECTIVE Our objective was to investigate the mechanism of hypercalciuria in FHHt. DESIGN AND SETTING We conducted a study of a large family with FHHt and WNK4 Q565E mutation and of control subjects at a referral medical center. SUBJECTS Forty-six members of a family with FHHt and WNK4 Q565E mutation, 23 of them affected, and 12 control subjects participated. MAIN OUTCOME MEASURES Urinary calcium and sodium concentrations, endogenous lithium clearance, age of hypertension appearance were assessed. RESULTS In 40 urine samples of 20 affected subjects, urinary calcium was correlated to urinary sodium (r = 0.567; P = 0.0001). In 28 urinary samples of 22 unaffected members, no correlation was found (r = 0.285; P = 0.14). Mean ratio of urinary calcium to urinary sodium was 2.7-fold higher in affected compared with unaffected members (58.7 +/- 25.9 vs. 22.1 +/- 14.0 micromol/mmol, P < 0.0001). Endogenous lithium clearance in eight affected members was about 50% lower than in 12 controls (16.2 +/- 7.7 vs. 28.8 +/- 9.8 ml/min, P = 0.0073). Hypertension was detected in males 12 yr earlier than in females (26.0 +/- 7.5 vs. 37.9 +/- 11.3 yr; P = 0.031). CONCLUSIONS Hypercalciuria in FHHt seems to be dependent on urinary sodium. According to molecular studies, FHHt patients are presumed to have increased distal nephron sodium reabsorption and therefore decreased proximal reabsorption of sodium, lithium, and calcium. The observed decreased lithium clearance reflects probable abnormal renal handling of lithium, i.e. distal nephron lithium reabsorption. Therefore, hypercalciuria may result from proximal nephron aberration. Finally, earlier appearance of hypertension in males may be the result of sex-hormone activity.
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Affiliation(s)
- Haim Mayan
- Department of Medicine E, Sheba Medical Center, Tel Hashomer, Israel
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Zeng C, Villar VAM, Yu P, Zhou L, Jose PA. Reactive oxygen species and dopamine receptor function in essential hypertension. Clin Exp Hypertens 2009; 31:156-78. [PMID: 19330604 DOI: 10.1080/10641960802621283] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Essential hypertension is a major risk factor for stroke, myocardial infarction, and heart and kidney failure. Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones and humoral factors. However, the mechanisms leading to impaired dopamine receptor function in hypertension states are not clear. Compelling experimental evidence indicates a role of reactive oxygen species (ROS) in hypertension, and there are increasing pieces of evidence showing that in conditions associated with oxidative stress, which is present in hypertensive states, dopamine receptor effects, such as natriuresis, diuresis, and vasodilation, are impaired. The goal of this review is to present experimental evidence that has led to the conclusion that decreased dopamine receptor function increases ROS activity and vice versa. Decreased dopamine receptor function and increased ROS production, working in concert or independent of each other, contribute to the pathogenesis of essential hypertension.
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Affiliation(s)
- Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China.
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Affiliation(s)
- Paul W Sanders
- Division of Nephrology, Department of Medicine, 642 Lyons-Harrison Research Building, 1530 Third Ave, S, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
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Affiliation(s)
- Peter A. Doris
- From the Center for Human Genetics, Brown Foundation Institute for Molecular Medicine for the Prevention of Human Disease, University of Texas HSC at Houston
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Jin Y, Kuznetsova T, Tikhonoff V, Maillard M, Bochud M, Burnier M, Hasenkamp S, Brand E, Brand-Herrmann SM, Richart T, Staessen JA. Segmental Renal Sodium Handling in Relation to the Human
SAH
Gene. Hypertension 2008; 52:e12-3. [DOI: 10.1161/hypertensionaha.108.115642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Yu Jin
- Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium
| | - Tatiana Kuznetsova
- Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium
| | - Valérie Tikhonoff
- Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
| | - Marc Maillard
- Division of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | - Murielle Bochud
- Division of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | - Michel Burnier
- Division of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | - Sandra Hasenkamp
- Nephrology and Hypertension, Department of Molecular Genetics of Cardiovascular Disease, University of Münster, Münster, Germany
| | - Eva Brand
- Nephrology and Hypertension, Department of Molecular Genetics of Cardiovascular Disease, University of Münster, Münster, Germany
| | - Stefan-Martin Brand-Herrmann
- Nephrology and Hypertension, Department of Molecular Genetics of Cardiovascular Disease, University of Münster, Münster, Germany
| | - Tom Richart
- Department of Epidemiology, Maastricht University, Maastricht, The Netherlands
| | - Jan A. Staessen
- Department of Epidemiology, Maastricht University, Maastricht, The Netherlands
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