|
1
|
Gao RR, Han C, Sui GY, Chen YB, Zhou L, Hu HZ, Wang YC, Liu Y, Li W. Huangqi and Danshen improve the chronic nephrotoxicity of cyclosporin A by regulating lipid metabolism. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156582. [PMID: 40056636 DOI: 10.1016/j.phymed.2025.156582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND The clinical application of cyclosporine A (CsA) is limited due to nephrotoxicity. Lipid metabolism disorders play important roles in renal injury, but their role in CsA nephrotoxicity is not yet clear. Huangqi (Astragalus mongholicus Bunge) and Danshen (Salvia miltiorrhiza Bunge) (HD) play roles in ameliorating the nephrotoxicity of CsA, but their mechanisms still need to be fully clarified. OBJECTIVE This study innovatively aimed to analyse the coexpression of renal proteins and serum metabolites for the identification of key pathways and targets. This study provides novel insight into the mechanism by which HD ameliorates CsA-induced nephrotoxicity. METHODS We utilized HD to intervene in both in vivo and in vitro nephrotoxicity models induced by CsA. For the in vivo experiments, we constructed a coexpression network of renal proteins and serum metabolites, which was used to screen for key pathways. To validate these findings, we knocked down key proteins in vivo. For the in vitro studies, we employed MTT, Transwell, flow cytometry, and immunofluorescence assays to monitor the epithelial-mesenchymal transition (EMT) of HK-2 cells. Additionally, we used electron microscopy and Seahorse assays to examine the effects of HD on mitochondrial structure and function. Furthermore, we overexpressed Ppara to further confirm the mechanism by which HD improves renal function. RESULTS HD can improve renal pathological damage and function; regulate blood lipids, inflammation and oxidative stress indicators; and reduce apoptosis in renal tissues. Joint protein and metabolomics analyses revealed that two lipid metabolism-related pathways (the PPAR signalling pathway and linoleic acid metabolism pathway) were coenriched, involving six differential proteins (Cyp2e1, Cyp4a10, Gk, Lpl, Ppara, and Pck1) and two differentially abundant metabolites (alpha-Dimorphecolic acid and 12,13-EpOME). Western blot was used to verify differentially expressed proteins. HD improved mitochondrial damage and lipid accumulation, as demonstrated by transmission electron microscopy (TEM) analysis and Oil Red O staining. Knockdown of the key protein Ppara affected the expression of ACOX1 and exacerbated RF. In vitro verification demonstrated that HD significantly inhibited CsA-induced EMT in HK-2 cells and improved mitochondrial structure and function. Ppara overexpression promoted HD-mediated regulation of mitochondrial function, reduced apoptosis, and improved HK-2 RF. CONCLUSION HD can ameliorate CsA nephrotoxicity through renal protein-serum metabolism coexpression, the PPAR signalling pathway, and linoleic acid metabolism. HD-induced upregulation of Ppara to regulate lipid metabolism, improve mitochondrial function and reduce apoptosis are important mechanisms. The Ppara/ACOX1/TGF-β1 axis may play an important role in this process. These findings offer potential targets for the future development of therapeutic strategies and novel drugs.
Collapse
Affiliation(s)
- Ran-Ran Gao
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Cong Han
- Nephropathy Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China.
| | - Gui-Yuan Sui
- Nephropathy Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Yi-Bing Chen
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Le Zhou
- Nephropathy Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Hong-Zhen Hu
- Nephropathy Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Yi-Chuan Wang
- Nephropathy Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Yao Liu
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China
| | - Wei Li
- Nephropathy Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, PR China.
| |
Collapse
|
|
2
|
Flores J, Pena C, Nugent K. Salt Sensitivity of Blood Pressure and the Role of the Immune System in Hypertension. Cardiol Rev 2024:00045415-990000000-00381. [PMID: 39679725 DOI: 10.1097/crd.0000000000000834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Salt-sensitive blood pressure is a clinical phenotype defined as exaggerated blood pressure responses to salt loading and salt depletion. This characteristic occurs in 25% of the general population and 50% of patients with hypertension and contributes to the pathogenesis of hypertension in some patients. Hypertension is associated with chronic inflammatory responses and has immune cell accumulation in several hypertensive target organs, including the brain, kidneys, heart, blood vessels, and the perivascular adipose tissue, and these cellular responses likely exacerbate hypertension. The different factors implicated in the pathogenesis of salt-sensitive hypertension include renin-angiotensin-aldosterone system dysfunction, aldosterone-dependent and aldosterone-independent mineralocorticoid receptor signaling, and the sympathetic nervous system dysfunction. Experimental studies have shown an important role of both innate and adaptive immune cells, especially lymphocytes, in angiotensin II-induced hypertension. The epithelial sodium channel (ENaC) allows entry of sodium into dendritic cells, and this leads to a sequence of events, including the production of reactive oxygen species, which activates the NLRP3 inflammasome and contributes to salt-sensitive hypertension through the amiloride-sensitive ENaC and isolevuglandin-adduct formation. This review summarizes the general aspects of salt sensitivity, focuses on the immunological/inflammatory factors involved in its development, considers general changes in microvasculature, and discusses management.
Collapse
Affiliation(s)
- Jackeline Flores
- From the Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
| | | | | |
Collapse
|
|
3
|
Shah SS, Fuller PJ, Young MJ, Yang J. Update on Low-Renin Hypertension: Current Understanding and Future Direction. Hypertension 2024; 81:2038-2048. [PMID: 39136130 DOI: 10.1161/hypertensionaha.124.23385] [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] [Indexed: 09/20/2024]
Abstract
Low-renin hypertension is common and affects 1 in 4 people with hypertension. Understanding the different causes and management of low-renin hypertension is becoming increasingly relevant as renin measurements are more widely ordered in clinical practice. Importantly, many people with low-renin hypertension do not fit traditional definitions of known causes, and the approach to management of these people is not unclear. This review provides an overview of our evolving understanding of the causes of low-renin hypertension, the expanding spectrums of pathophysiology, key differentiating characteristics, distinct management strategies, and highlights our knowledge gaps. It is important to distinguish the underlying pathophysiology of an individual with low-renin hypertension to individualize treatment.
Collapse
Affiliation(s)
- Sonali S Shah
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia (S.S.S., P.J.F., M.J.Y., J.Y.)
- Department of Endocrinology, Monash Health, Clayton, Victoria, Australia (S.S.S., P.J.F., J.Y.)
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia (S.S.S., P.J.F., J.Y.)
| | - Peter J Fuller
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia (S.S.S., P.J.F., M.J.Y., J.Y.)
- Department of Endocrinology, Monash Health, Clayton, Victoria, Australia (S.S.S., P.J.F., J.Y.)
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia (S.S.S., P.J.F., J.Y.)
| | - Morag J Young
- Baker Heart and Diabetes Institute, Prahran, Victoria, Australia (M.J.Y.)
| | - Jun Yang
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia (S.S.S., P.J.F., M.J.Y., J.Y.)
- Department of Endocrinology, Monash Health, Clayton, Victoria, Australia (S.S.S., P.J.F., J.Y.)
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia (S.S.S., P.J.F., J.Y.)
| |
Collapse
|
|
4
|
Bi X, Wang Y, Lin Y, Wang M, Li X. Genetic Evidence for Causal Relationships between Plasma Eicosanoid Levels and Cardiovascular Disease. Metabolites 2024; 14:294. [PMID: 38921429 PMCID: PMC11206149 DOI: 10.3390/metabo14060294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
Cardiovascular diseases are the most common causes of mortality and disability worldwide. Eicosanoids are a group of bioactive metabolites that are mainly oxidized by arachidonic acid. Eicosanoids play a diverse role in cardiovascular diseases, with some exerting beneficial effects while others have detrimental consequences. However, a causal relationship between eicosanoid levels and cardiovascular disease remains unclear. Six single nucleotide polymorphisms (SNPs) with strong associations with plasma eicosanoid levels were selected. Summary-level data for cardiovascular disease were obtained from publicly available genome-wide association studies. A two-sample MR analysis identified that plasma eicosanoid levels were inversely correlated with unstable angina pectoris (OR 1.06; 95% CI 1-1.12; p = 0.04), myocardial infarction (OR 1.05; 95% CI 1.02-1.09; p = 0.005), ischemia stroke (OR 1.05; 95% CI 1-1.11; p = 0.047), transient ischemic attack (OR 1.03; 95% CI 1-1.07; p = 0.042), heart failure (OR 1.03; 95% CI 1.01-1.05; p = 0.011), and pulmonary embolism (OR 1.08; 95% CI 1.02-1.14; p = 1.69 × 10-6). In conclusion, our data strongly suggest a genetic causal link between high plasma eicosanoid levels and an increased cardiovascular disease risk. This study provides genetic evidence for treating cardiovascular diseases.
Collapse
Affiliation(s)
- Xukun Bi
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Yiran Wang
- Department of Nursing, No. 906 Hospital of People’s Liberation Army, Ningbo 315000, China
| | - Yangjun Lin
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Meihui Wang
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Xiaoting Li
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| |
Collapse
|
|
5
|
Ertuglu LA, Mutchler AP, Jamison S, Laffer CL, Saleem M, Blackwell DJ, Kryshtal DO, Sahinoz M, Sheng Q, Wanjalla CN, Pakala S, Justin Y, Gutierrez OM, Kleyman TR, Knollmann BC, Ikizler TA, Kirabo A. Eicosanoid-Regulated Myeloid ENaC and Isolevuglandin Formation in Human Salt-Sensitive Hypertension. Hypertension 2024; 81:516-529. [PMID: 37675576 PMCID: PMC10918035 DOI: 10.1161/hypertensionaha.123.21285] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/15/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND The mechanisms by which salt increases blood pressure in people with salt sensitivity remain unclear. Our previous studies found that high sodium enters antigen-presenting cells (APCs) via the epithelial sodium channel and leads to the production of isolevuglandins and hypertension. In the current mechanistic clinical study, we hypothesized that epithelial sodium channel-dependent isolevuglandin-adduct formation in APCs is regulated by epoxyeicosatrienoic acids (EETs) and leads to salt-sensitive hypertension in humans. METHODS Salt sensitivity was assessed in 19 hypertensive subjects using an inpatient salt loading and depletion protocol. Isolevuglandin-adduct accumulation in APCs was analyzed using flow cytometry. Gene expression in APCs was analyzed using cellular indexing of transcriptomes and epitopes by sequencing analysis of blood mononuclear cells. Plasma and urine EETs were measured using liquid chromatography-mass spectrometry. RESULTS Baseline isolevuglandin+ APCs correlated with higher salt-sensitivity index. Isolevuglandin+ APCs significantly decreased from salt loading to depletion with an increasing salt-sensitivity index. We observed that human APCs express the epithelial sodium channel δ subunit, SGK1 (salt-sensing kinase serum/glucocorticoid kinase 1), and cytochrome P450 2S1. We found a direct correlation between baseline urinary 14,15 EET and salt-sensitivity index, whereas changes in urinary 14,15 EET negatively correlated with isolevuglandin+ monocytes from salt loading to depletion. Coincubation with 14,15 EET inhibited high-salt-induced increase in isolevuglandin+ APC. CONCLUSIONS Isolevuglandin formation in APCs responds to acute changes in salt intake in salt-sensitive but not salt-resistant people with hypertension, and this may be regulated by renal 14,15 EET. Baseline levels of isolevuglandin+ APCs or urinary 14,15 EET may provide diagnostic tools for salt sensitivity without a protocol of salt loading.
Collapse
Affiliation(s)
- Lale A. Ertuglu
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ashley Pitzer Mutchler
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
| | - S Jamison
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
- Meharry Medical College Nashville, Nashville, TN, United States
| | - Cheryl L. Laffer
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
| | - Mohammad Saleem
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
| | - Daniel J. Blackwell
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
| | - Dmytro O. Kryshtal
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
| | - Melis Sahinoz
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Quanhu Sheng
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Celestine N. Wanjalla
- Department of Internal Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center Nashville, TN, USA
| | - Suman Pakala
- Department of Internal Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center Nashville, TN, USA
| | - Yu Justin
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Orlando M Gutierrez
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Thomas R. Kleyman
- Departments of Medicine, Cell Biology, Pharmacology, and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Björn C. Knollmann
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
| | - T. Alp Ikizler
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Annet Kirabo
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center Nashville, TN, USA
- Vanderbilt Center for Immunobiology (VCI)
- Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4)
- Vanderbilt Institute for Global Health (VIGH)
| |
Collapse
|
|
6
|
Watanabe K, Kondo M, Ikenaka Y, Nakayama SMM, Ishizuka M. A Comparative Genomic and Phylogenetic Investigation of the Xenobiotic Metabolism Enzymes of Cytochrome P450 in Elephants Shows Loss in CYP2E and CYP4A. Animals (Basel) 2023; 13:1939. [PMID: 37370449 DOI: 10.3390/ani13121939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/04/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Cytochrome P450 is an important enzyme that metabolizes a variety of chemicals, including exogenous substances, such as drugs and environmental chemicals, and endogenous substances, such as steroids, fatty acids, and cholesterol. Some CYPs show interspecific differences in terms of genetic variation. As little is known about the mechanisms of elephant metabolism, we carried out a comparative genomic and phylogenetic analysis of CYP in elephants. Our results suggest that elephant CYP genes have undergone independent duplication, particularly in the CYP2A, CYP2C, and CYP3A genes, a unique cluster specific to elephant species. However, while CYP2E and CYP4A were conserved in other Afrotheria taxa, their decay in elephants resulted in genetic dysfunction (pseudogene). These findings outline several remarkable characteristics of elephant CYP1-4 genes and provide new insights into elephant xenobiotic metabolism. Further functional investigations are necessary to characterize elephant CYP, including expression patterns and interactions with drugs and sensitivities to other chemicals.
Collapse
Affiliation(s)
- Kanami Watanabe
- Laboratory of Toxicology, Department of Environmental Veterinary Science, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Mitsuki Kondo
- National Institute for Environmental Studies (NIES) Biodiversity Division, Ecological Risk Assessment and Control Section, Tsukuba 305-8506, Japan
| | - Yoshinori Ikenaka
- Laboratory of Toxicology, Department of Environmental Veterinary Science, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
- Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom 2520, South Africa
- Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
- One Health Research Center, Hokkaido University, Sapporo 060-0818, Japan
| | - Shouta M M Nakayama
- Laboratory of Toxicology, Department of Environmental Veterinary Science, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
- Biomedical Sciences Department, School of Veterinary Medicine, The University of Zambia, P.O. Box 32379, Lusaka 10101, Zambia
| | - Mayumi Ishizuka
- Laboratory of Toxicology, Department of Environmental Veterinary Science, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| |
Collapse
|
|
7
|
Ranea-Robles P, Houten SM. The biochemistry and physiology of long-chain dicarboxylic acid metabolism. Biochem J 2023; 480:607-627. [PMID: 37140888 PMCID: PMC10214252 DOI: 10.1042/bcj20230041] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/05/2023]
Abstract
Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these pathways and forms dicarboxylic acids as products. These dicarboxylic acids are metabolized through peroxisomal β-oxidation representing an alternative pathway, which could potentially limit the toxic effects of fatty acid accumulation. Although dicarboxylic acid metabolism is highly active in liver and kidney, its role in physiology has not been explored in depth. In this review, we summarize the biochemical mechanism of the formation and degradation of dicarboxylic acids through ω- and β-oxidation, respectively. We will discuss the role of dicarboxylic acids in different (patho)physiological states with a particular focus on the role of the intermediates and products generated through peroxisomal β-oxidation. This review is expected to increase the understanding of dicarboxylic acid metabolism and spark future research.
Collapse
Affiliation(s)
- Pablo Ranea-Robles
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Sander M Houten
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, U.S.A
| |
Collapse
|
|
8
|
Abstract
Hypertension is a major healthcare issue that afflicts one in every three adults worldwide and contributes to cardiovascular diseases, morbidity and mortality. Bioactive lipids contribute importantly to blood pressure regulation via actions on the vasculature, kidney, and inflammation. Vascular actions of bioactive lipids include blood pressure lowering vasodilation and blood pressure elevating vasoconstriction. Increased renin release by bioactive lipids in the kidney is pro-hypertensive whereas anti-hypertensive bioactive lipid actions result in increased sodium excretion. Bioactive lipids have pro-inflammatory and anti-inflammatory actions that increase or decrease reactive oxygen species and impact vascular and kidney function in hypertension. Human studies provide evidence that fatty acid metabolism and bioactive lipids contribute to sodium and blood pressure regulation in hypertension. Genetic changes identified in humans that impact arachidonic acid metabolism have been associated with hypertension. Arachidonic acid cyclooxygenase, lipoxygenase and cytochrome P450 metabolites have pro-hypertensive and anti-hypertensive actions. Omega-3 fish oil fatty acids eicosapentaenoic acid and docosahexaenoic acid are known to be anti-hypertensive and cardiovascular protective. Lastly, emerging fatty acid research areas include blood pressure regulation by isolevuglandins, nitrated fatty acids, and short chain fatty acids. Taken together, bioactive lipids are key contributors to blood pressure regulation and hypertension and their manipulation could decrease cardiovascular disease and associated morbidity and mortality.
Collapse
Affiliation(s)
- John D Imig
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
| |
Collapse
|
|
9
|
Hannon SL, Ding X. Assessing cytochrome P450 function using genetically engineered mouse models. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 95:253-284. [PMID: 35953157 PMCID: PMC10544722 DOI: 10.1016/bs.apha.2022.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The ability to knock out and/or humanize different genes in experimental animals, globally or in cell- and tissue-specific patterns, has revolutionized scientific research in many areas. Genetically engineered mouse models, including knockout models, transgenic models, and humanized models, have played important roles in revealing the in vivo functions of various cytochrome P450 (CYP) enzymes. These functions are very diverse, ranging from the biotransformation of drugs and other xenobiotics, events that often dictate their pharmacokinetic or toxicokinetic properties and the associated therapeutic or adverse actions, to the metabolism of endogenous compounds, such as steroid hormones and other bioactive substances, that may determine susceptibility to many diseases, such as cancer and metabolic diseases. In this review, we provide a comprehensive list of Cyp-knockout, human CYP-transgenic, and CYP-humanized mouse models that target genes in the CYP1-4 gene families, and highlight their utility in assessing the in vivo metabolism, bioactivation, and toxicity of various xenobiotic compounds, including therapeutic agents and chemical carcinogens. We aim to showcase the advantages of utilizing these mouse models for in vivo drug metabolism and toxicology studies, and to encourage and facilitate greater utility of engineered mouse models to further improve our knowledge of the in vivo functions of various P450 enzymes, which is integral to our ability to develop safer and more effective therapeutics and to identify individuals predisposed to adverse drug reactions or environmental diseases.
Collapse
Affiliation(s)
- Sarrah L Hannon
- Department of Pharmacology and Toxicology, Ken R. Coit College of Pharmacy, The University of Arizona, Tucson, AZ, United States
| | - Xinxin Ding
- Department of Pharmacology and Toxicology, Ken R. Coit College of Pharmacy, The University of Arizona, Tucson, AZ, United States.
| |
Collapse
|
|
10
|
Imig JD. Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury. ADVANCES IN PHARMACOLOGY 2022; 94:27-55. [PMID: 35659375 PMCID: PMC10105514 DOI: 10.1016/bs.apha.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression. Furthermore, evidence in human and experimental animal studies have found that decreased EET levels contribute to hypertension and kidney diseases. Consequently, EET mimics/analogs have been developed as a potential therapeutic for hypertension and acute and chronic kidney diseases. Their development has resulted in EET analogs that are orally active with favorable pharmacological profiles. Analogs for 8,9-EET, 11,12-EET, and 14,15-EET have been tested in several hypertension and kidney disease animal models. More recently, kidney targeted EET analogs have been synthesized and tested against drug-induced nephrotoxicity. Experimental evidence has demonstrated compelling therapeutic potential for EET analogs to oppose cardiovascular and kidney diseases. These EET analogs lower blood pressure, decrease kidney inflammation, improve vascular endothelial function, and decrease kidney fibrosis and apoptosis. Overall, these preclinical studies support the likelihood that EET analogs will advance to clinical trials for hypertension and associated comorbidities or acute and chronic kidney diseases.
Collapse
Affiliation(s)
- John D Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States.
| |
Collapse
|
|
11
|
Wu Y, Xu H, Tu X, Gao Z. The Role of Short-Chain Fatty Acids of Gut Microbiota Origin in Hypertension. Front Microbiol 2021; 12:730809. [PMID: 34650536 PMCID: PMC8506212 DOI: 10.3389/fmicb.2021.730809] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022] Open
Abstract
Hypertension is a significant risk factor for cardiovascular and cerebrovascular diseases, and its development involves multiple mechanisms. Gut microbiota has been reported to be closely linked to hypertension. Short-chain fatty acids (SCFAs)-the metabolites of gut microbiota-participate in hypertension development through various pathways, including specific receptors, immune system, autonomic nervous system, metabolic regulation and gene transcription. This article reviews the possible mechanisms of SCFAs in regulating blood pressure and the prospects of SCFAs as a target to prevent and treat hypertension.
Collapse
Affiliation(s)
- Yeshun Wu
- Department of Cardiology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Hongqing Xu
- Department of Cardiology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Xiaoming Tu
- Department of Cardiology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Zhenyan Gao
- Department of Cardiology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| |
Collapse
|
|
12
|
Wu J, Lai G, Chen F, Zhang B, Zhao Y. Renal NKCC2 Is Dual Regulated by the Synergy of 20-HETE and High-Fat Diet in CYP4F2 Transgenic Mice. Kidney Blood Press Res 2021; 46:601-612. [PMID: 34320496 DOI: 10.1159/000517382] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/22/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION 20-Hydroxyeicosatetraenoic acid (20-HETE) is the metabolite of cytochrome P450, which modulates blood pressure by inhibiting renal sodium transport. However, the molecular mechanisms underlying the role of 20-HETE in the development of obesity-related hypertension remain unclear, necessitating this study. METHODS Cytochrome P450 4F2 (CYP4F2) transgenic mice fed high-fat diet (HFD) were used as research animal models. The expression of renal ion transport molecules targeted by 20-HETE was evaluated by real-time PCR and Western blot (WB). The regulatory effect of 20-HETE and HFD on renal Na+-K+-2Cl- cotransporter, isoform 2 (NKCC2) was explored by immunoprecipitation, WB, and luciferase assay. RESULTS A 2-week HFD feeding dramatically decreased protein abundance but increased renal NKCC2 mRNA expression in CYP4F2 transgenic mice. The decrease in NKCC2 protein was demonstrated to be due to ubiquitination induced by the synergy between 20-HETE and HFD. The increased PPAR-γ protein in CYP4F2 transgenic mice fed HFD and the activation of rosiglitazone on the luciferase reporter construct of the NKCC2 promoter demonstrated that the increase in NKCC2 mRNA in CYP4F2 transgenic mice fed HFD was a consequence of elevated PPAR-γ protein induced by the synergy between 20-HETE and HFD. CONCLUSIONS Our data demonstrated that the synergy between 20-HETE and HFD could decrease NKCC2 protein via posttranslational ubiquitination, which was thought to be the main mechanism underlying the short-term effect in response to HFD and might be responsible for the adaptive modulation of renal NKCC2 to resist sodium retention. Moreover, the increased NKCC2 mRNA expression via PPAR-γ-induced transcriptional regulation was thought to be the main mechanism underlying the long-term effect in response to HFD and plays a pivotal role in the development of obesity-related hypertension.
Collapse
Affiliation(s)
- Jingjing Wu
- Department of Medical Genetics, School of Life Sciences, China Medical University, Shenyang, China,
| | - Guangrui Lai
- Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fangjie Chen
- Department of Medical Genetics, School of Life Sciences, China Medical University, Shenyang, China
| | - Bijun Zhang
- Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yanyan Zhao
- Department of Medical Genetics, School of Life Sciences, China Medical University, Shenyang, China
| |
Collapse
|
|
13
|
Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Van Beusecum JP, Patrick DM, Smart CD, Kleyman TR, Kingery J, Peck RN, Laffer CL, Kirabo A. Hypertension: Do Inflammation and Immunity Hold the Key to Solving this Epidemic? Circ Res 2021; 128:908-933. [PMID: 33793336 PMCID: PMC8023750 DOI: 10.1161/circresaha.121.318052] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.
Collapse
Affiliation(s)
- Meena S. Madhur
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center
- Department of Molecular Physiology and Biophysics, Vanderbilt University
| | - Fernando Elijovich
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Matthew R. Alexander
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center
| | - Ashley Pitzer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jeanne Ishimwe
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Justin P. Van Beusecum
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - David M. Patrick
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center
| | - Charles D. Smart
- Department of Molecular Physiology and Biophysics, Vanderbilt University
| | - Thomas R. Kleyman
- Departments of Medicine, Cell Biology, Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Justin Kingery
- Center for Global Health, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania
| | - Robert N. Peck
- Center for Global Health, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania
- Mwanza Intervention Trials Unit (MITU), Mwanza, Tanzania
| | - Cheryl L. Laffer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University
| |
Collapse
|
|
14
|
Elijovich F, Kirabo A, Laffer CL. Hypothesis: Unrecognized actions of ENaC blockade in improving refractory-resistant hypertension and residual cardiovascular risk. Int J Cardiol Hypertens 2020; 7:100048. [PMID: 33447773 PMCID: PMC7803029 DOI: 10.1016/j.ijchy.2020.100048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 09/04/2020] [Indexed: 11/16/2022] Open
|
|
15
|
Luo Y, Liu JY. Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer. Front Pharmacol 2020; 11:580897. [PMID: 33192522 PMCID: PMC7658919 DOI: 10.3389/fphar.2020.580897] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ω-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.
Collapse
Affiliation(s)
- Ying Luo
- Department of Clinical Laboratory, Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Jun-Yan Liu
- Center for Novel Target & Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
16
|
Imig JD, Jankiewicz WK, Khan AH. Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture. Hypertension 2020; 76:3-15. [PMID: 32475311 PMCID: PMC7448548 DOI: 10.1161/hypertensionaha.120.13898] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.
Collapse
Affiliation(s)
- John D Imig
- From the Department of Pharmacology and Toxicology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee
| | - Wojciech K Jankiewicz
- From the Department of Pharmacology and Toxicology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee
| | - Abdul H Khan
- From the Department of Pharmacology and Toxicology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee
| |
Collapse
|
|
17
|
Wang MX, Wang LJ, Xiao Y, Zhang DD, Duan XP, Wang WH. Epoxyeicosatrienoic acid metabolites inhibit Kir4.1/Kir5.1 in the distal convoluted tubule. Am J Physiol Renal Physiol 2020; 318:F1369-F1376. [PMID: 32308018 PMCID: PMC7311705 DOI: 10.1152/ajprenal.00018.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/12/2020] [Accepted: 04/13/2020] [Indexed: 11/22/2022] Open
Abstract
Cytochrome P-450 (Cyp) epoxygenase-dependent metabolites of arachidonic acid (AA) have been shown to inhibit renal Na+ transport, and inhibition of Cyp-epoxygenase is associated with salt-sensitive hypertension. We used the patch-clamp technique to examine whether Cyp-epoxygenase-dependent AA metabolites inhibited the basolateral 40-pS K+ channel (Kir4.1/Kir5.1) in the distal convoluted tubule (DCT). Application of AA inhibited the basolateral 40-pS K+ channel in the DCT. The inhibitory effect of AA on the 40-pS K+ channel was specific because neither linoleic nor oleic acid was able to mimic the effect of AA on the K+ channel. Inhibition of Cyp-monooxygenase with N-methylsulfonyl-12,12-dibromododec-11-enamide or inhibition of cyclooxygenase with indomethacin failed to abolish the inhibitory effect of AA on the 40-pS K+ channel. However, the inhibition of Cyp-epoxygenase with N-methylsulfonyl-6-(propargyloxyphenyl)hexanamide abolished the effect of AA on the 40-pS K+ channel in the DCT. Moreover, addition of either 11,12-epoxyeicosatrienoic acid (EET) or 14,15-EET also inhibited the 40-pS K+ channel in the DCT. Whole cell recording demonstrated that application of AA decreased, whereas N-methylsulfonyl-6-(propargyloxyphenyl)hexanamide treatment increased, Ba2+-sensitive K+ currents in the DCT. Finally, application of 14,15-EET but not AA was able to inhibit the basolateral 40-pS K+ channel in the DCT of Cyp2c44-/- mice. We conclude that Cyp-epoxygenase-dependent AA metabolites inhibit the basolateral Kir4.1/Kir5.1 in the DCT and that Cyp2c44-epoxygenase plays a role in the regulation of the basolateral K+ channel in the mouse DCT.
Collapse
MESH Headings
- 8,11,14-Eicosatrienoic Acid/analogs & derivatives
- 8,11,14-Eicosatrienoic Acid/metabolism
- 8,11,14-Eicosatrienoic Acid/pharmacology
- Amides/pharmacology
- Animals
- Arachidonic Acid/metabolism
- Arachidonic Acid/pharmacology
- Cytochrome P450 Family 2/antagonists & inhibitors
- Cytochrome P450 Family 2/genetics
- Cytochrome P450 Family 2/metabolism
- Enzyme Inhibitors/pharmacology
- Kidney Tubules, Distal/drug effects
- Kidney Tubules, Distal/metabolism
- Male
- Membrane Potentials
- Mice, 129 Strain
- Mice, Knockout
- Potassium Channel Blockers/metabolism
- Potassium Channel Blockers/pharmacology
- Potassium Channels, Inwardly Rectifying/antagonists & inhibitors
- Potassium Channels, Inwardly Rectifying/metabolism
Collapse
Affiliation(s)
- Ming-Xiao Wang
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zunyi, Guizhou, China
| | - Li-Jun Wang
- Department of Physiology, Harbin Medical University, Harbin, China
| | - Yu Xiao
- Department of Physiology, Qiqihar Medical College, Heilongjiang, China
| | - Dan-Dan Zhang
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Xin-Peng Duan
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Wen-Hui Wang
- Department of Pharmacology, New York Medical College, Valhalla, New York
| |
Collapse
|
|
18
|
Agba S, Hanif A, Edin ML, Zeldin DC, Nayeem MA. Cyp2j5-Gene Deletion Affects on Acetylcholine and Adenosine-Induced Relaxation in Mice: Role of Angiotensin-II and CYP-Epoxygenase Inhibitor. Front Pharmacol 2020; 11:27. [PMID: 32116704 PMCID: PMC7014568 DOI: 10.3389/fphar.2020.00027] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 01/10/2020] [Indexed: 12/30/2022] Open
Abstract
Previously, we showed vascular endothelial overexpression of human-CYP2J2 enhances coronary reactive hyperemia in Tie2-CYP2J2 Tr mice, and eNOS−/− mice had overexpression of CYP2J-epoxygenase with adenosine A2A receptor-induced enhance relaxation, but we did not see the response in CYP2J-epoxygenase knockout mice. Therefore, we hypothesized that Cyp2j5-gene deletion affects acetylcholine- and 5'-N-ethylcarboxamidoadenosine (NECA) (adenosine)-induced relaxation and their response is partially inhibited by angiotensin-II (Ang-II) in mice. Acetylcholine (Ach)-induced response was tested with N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH, CYP-epoxygenase inhibitor; 10−5M) and Ang-II (10−6M). In Cyp2j5−/− mice, ACh-induced relaxation was different from C57Bl/6 mice, at 10−5 M (76.1 ± 3.3 vs. 58.3 ± 5.2, P < 0.05). However, ACh-induced relaxation was not blocked by MS-PPOH in Cyp2j5−/−: 58.5 ± 5.0%, P > 0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, P < 0.05, and Ang-II reduces ACh-induced relaxation in both Cyp2j5−/− and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, P <0.05). In addition, NECA-induced response was tested with Ang-II. In Cyp2j5−/− mice, NECA-induced response was not different from C57Bl/6 mice at 10−5M (23.1 ± 2.1 vs. 21.1 ± 3.8, P > 0.05). However, NECA-induced response was reduced by Ang-II in both Cyp2j5−/− and C57Bl/6 mice (−10.8 ± 2.3% and 3.2 ± 2.7, P < 0.05). Data suggest that ACh-induced relaxation in Cyp2j5−/− mice depends on nitric oxide (NO) but not CYP-epoxygenases, and the NECA-induced different response in male vs. female Cyp2j5−/− mice when Ang-II treated.
Collapse
Affiliation(s)
- Stephanie Agba
- Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, United States
| | - Ahmad Hanif
- Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, United States
| | - Matthew L Edin
- Division of Intramural Research, NIEHS/NIH, Durham, NC, United States
| | - Darryl C Zeldin
- Division of Intramural Research, NIEHS/NIH, Durham, NC, United States
| | - Mohammed A Nayeem
- Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, United States
| |
Collapse
|
|
19
|
Fleming I. New Lipid Mediators in Retinal Angiogenesis and Retinopathy. Front Pharmacol 2019; 10:739. [PMID: 31333461 PMCID: PMC6624440 DOI: 10.3389/fphar.2019.00739] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 06/07/2019] [Indexed: 12/31/2022] Open
Abstract
Retinal diseases associated with vascular destabilization and the inappropriate proliferation of retinal endothelial cells have major consequences on the retinal vascular network. In extreme cases, the development of hypoxia, the upregulation of growth factors, and the hyper-proliferation of unstable capillaries can result in bleeding and vision loss. While anti-vascular endothelial growth factor therapy and laser retinal photocoagulation can be used to treat the symptoms of late stage disease, there is currently no treatment available that can prevent disease progression. Cytochrome P450 enzymes metabolize endogenous substrates (polyunsaturated fatty acids) to bioactive fatty acid epoxides that demonstrate biological activity with generally protective/anti-inflammatory and insulin-sensitizing effects. These epoxides are further metabolized by the soluble epoxide hydrolase (sEH) to fatty acid diols, high concentrations of which have vascular destabilizing effects. Recent studies have identified increased sEH expression and activity and the subsequent generation of the docosahexaenoic acid-derived diol; 19,20-dihydroxydocosapentaenoic acid, as playing a major role in the development of diabetic retinopathy. This review summarizes current understanding of the roles of cytochrome P450 enzyme and sEH–derived PUFA mediators in retinal disease.
Collapse
Affiliation(s)
- Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt, Germany.,German Centre for Cardiovascular Research (DZHK) partner site RheinMain, Frankfurt, Germany
| |
Collapse
|
|
20
|
Zilbermint M, Hannah-Shmouni F, Stratakis CA. Genetics of Hypertension in African Americans and Others of African Descent. Int J Mol Sci 2019; 20:ijms20051081. [PMID: 30832344 PMCID: PMC6429313 DOI: 10.3390/ijms20051081] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/19/2019] [Accepted: 02/21/2019] [Indexed: 02/07/2023] Open
Abstract
Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.
Collapse
Affiliation(s)
- Mihail Zilbermint
- Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, BG 31 RM 2A46, 31 Center Dr, Bethesda, MD 20892, USA.
- Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
- Johns Hopkins Community Physicians at Suburban Hospital, Bethesda, MD 20814, USA.
- Johns Hopkins University Carey Business School, Baltimore, MD 21202, USA.
| | - Fady Hannah-Shmouni
- Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, BG 31 RM 2A46, 31 Center Dr, Bethesda, MD 20892, USA.
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, BG 31 RM 2A46, 31 Center Dr, Bethesda, MD 20892, USA.
| |
Collapse
|
|
21
|
Abstract
Therapeutics for arachidonic acid pathways began with the development of non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX). The enzymatic pathways and arachidonic acid metabolites and respective receptors have been successfully targeted and therapeutics developed for pain, inflammation, pulmonary and cardiovascular diseases. These drugs target the COX and lipoxygenase pathways but not the third branch for arachidonic acid metabolism, the cytochrome P450 (CYP) pathway. Small molecule compounds targeting enzymes and CYP epoxy-fatty acid metabolites have evolved rapidly over the last two decades. These therapeutics have primarily focused on inhibiting soluble epoxide hydrolase (sEH) or agonist mimetics for epoxyeicosatrienoic acids (EET). Based on preclinical animal model studies and human studies, major therapeutic indications for these sEH inhibitors and EET mimics/analogs are renal and cardiovascular diseases. Novel small molecules that inhibit sEH have advanced to human clinical trials and demonstrate promise for cardiovascular diseases. Challenges remain for sEH inhibitor and EET analog drug development; however, there is a high likelihood that a drug that acts on this third branch of arachidonic acid metabolism will be utilized to treat a cardiovascular or kidney disease in the next decade.
Collapse
Affiliation(s)
- John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
| |
Collapse
|
|
22
|
Capdevila JH, Falck JR. The arachidonic acid monooxygenase: from biochemical curiosity to physiological/pathophysiological significance. J Lipid Res 2018; 59:2047-2062. [PMID: 30154230 PMCID: PMC6210905 DOI: 10.1194/jlr.r087882] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/10/2018] [Indexed: 12/19/2022] Open
Abstract
The initial studies of the metabolism of arachidonic acid (AA) by the cytochrome P450 (P450) hemeproteins sought to: a) elucidate the roles for these enzymes in the metabolism of endogenous pools of the FA, b) identify the P450 isoforms involved in AA epoxidation and ω/ω-1 hydroxylation, and c) explore the biological activities of their metabolites. These early investigations provided a foundation for subsequent efforts to establish the physiological relevance of the AA monooxygenase and its contributions to the pathophysiology of, for example, cancer, diabetes, hypertension, inflammation, nociception, and vascular disease. This retrospective analyzes the history of some of these efforts, with emphasis on genetic studies that identified roles for the murine Cyp4a and Cyp2c genes in renal and vascular physiology and the pathophysiology of hypertension and cancer. Wide-ranging investigations by laboratories worldwide, including the authors, have established a better appreciation of the enzymology, genetics, and physiologic roles for what is now known as the third branch of the AA cascade. Combined with the development of analytical and pharmacological tools, including robust synthetic agonists and antagonists of the major metabolites, we stand at the threshold of novel therapeutic approaches for the treatment of renal injury, pain, hypertension, and heart disease.
Collapse
Affiliation(s)
- Jorge H Capdevila
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - John R Falck
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390
| |
Collapse
|
|
23
|
Beaini S, Saliba Y, Hajal J, Smayra V, Bakhos JJ, Joubran N, Chelala D, Fares N. VEGF-C attenuates renal damage in salt-sensitive hypertension. J Cell Physiol 2018; 234:9616-9630. [PMID: 30378108 DOI: 10.1002/jcp.27648] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 10/02/2018] [Indexed: 12/18/2022]
Abstract
Salt-sensitive hypertension is a major risk factor for renal impairment leading to chronic kidney disease. High-salt diet leads to hypertonic skin interstitial volume retention enhancing the activation of the tonicity-responsive enhancer-binding protein (TonEBP) within macrophages leading to vascular endothelial growth factor C (VEGF-C) secretion and NOS3 modulation. This promotes skin lymphangiogenesis and blood pressure regulation. Whether VEGF-C administration enhances renal and skin lymphangiogenesis and attenuates renal damage in salt-sensitive hypertension remains to be elucidated. Hypertension was induced in BALB/c mice by a high-salt diet. VEGF-C was administered subcutaneously to high-salt-treated mice as well as control animals. Analyses of kidney injury, inflammation, fibrosis, and biochemical markers were performed in vivo. VEGF-C reduced plasma inflammatory markers in salt-treated mice. In addition, VEGF-C exhibited a renal anti-inflammatory effect with the induction of macrophage M2 phenotype, followed by reductions in interstitial fibrosis. Antioxidant enzymes within the kidney as well as urinary RNA/DNA damage markers were all revelatory of abolished oxidative stress under VEGF-C. Furthermore, VEGF-C decreased the urinary albumin/creatinine ratio and blood pressure as well as glomerular and tubular damages. These improvements were associated with enhanced TonEBP, NOS3, and lymphangiogenesis within the kidney and skin. Our data show that VEGF-C administration plays a major role in preserving renal histology and reducing blood pressure. VEGF-C might constitute an interesting potential therapeutic target for improving renal remodeling in salt-sensitive hypertension.
Collapse
Affiliation(s)
- Shadia Beaini
- Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Youakim Saliba
- Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Joelle Hajal
- Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Viviane Smayra
- Divisions of Nephrology and Anatomopathology, Faculty of Medicine, Hotel Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - Jules-Joel Bakhos
- Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Najat Joubran
- Division of Nephrology, Faculty of Medicine and Medical Sciences, Saint Georges Hospital, Balamand University, Beirut, Lebanon
| | - Dania Chelala
- Divisions of Nephrology and Anatomopathology, Faculty of Medicine, Hotel Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - Nassim Fares
- Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| |
Collapse
|
|
24
|
Guo Z, Johnson V, Barrera J, Porras M, Hinojosa D, Hernández I, McGarrah P, Potter DA. Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them. Cancer Metastasis Rev 2018; 37:409-423. [DOI: 10.1007/s10555-018-9749-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
|
|
25
|
Elijovich F, Milne GL, Brown NJ, Laniado-Schwartzman M, Laffer CL. Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects. Hypertension 2017; 71:346-355. [PMID: 29279315 DOI: 10.1161/hypertensionaha.117.10392] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 10/14/2017] [Accepted: 11/28/2017] [Indexed: 11/16/2022]
Abstract
We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na+/24 hours, HiNa) and depletion (10 mEq Na+/24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrienoic acids) were considered the total converted 14,15-urine pool. We report ultra-performance liquid chromatography/tandem mass spectrometry plasma EETs, DHETs, and their sum (plasma total pool) for the 3 regioisomers (8,9-, 11,12-, 14,15-) and their sum (08,15-). In salt-resistant subjects, urine total pool was unchanged by HiNa, decreased by LoNa, and correlated with urine sodium excretion, fractional excretion of Na+, and Na+/K+ ratio for the 3 days of the experiment combined (P<0.03). In contrast, plasma total pool increased in LoNa and did not correlate with natriuresis or Na+/K+ ratio but showed correlations between EETs, blood pressures, and catecholamines and between DHETs and aldosterone (P<0.03). Urine total pool of salt-sensitive was lower than that of salt-resistant subjects in certain phases of the experiment, lacked responses to changes in salt balance, and exhibited limited correlations with natriuresis and Na+/K+ ratio during LoNa only. Plasma total pool of salt-sensitive was lower than in salt-resistant subjects and did not correlate with blood pressures or aldosterone but did with catecholamines. We conclude that the urine total pool reflects a renal pool involved in regulation of natriuresis, whereas the plasma total pools are of systemic origin, uninvolved in Na+ excretion, perhaps contributing to regulation of vascular tone. Data suggest that abnormalities in EETs in salt-sensitive subjects participate in their renal or vascular dysfunction, which has potential therapeutic implications.
Collapse
Affiliation(s)
- Fernando Elijovich
- From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.E., G.L.M., N.J.B., C.L.L.); and Department of Pharmacology, New York Medical College, Valhalla (M.L.-S.).
| | - Ginger L Milne
- From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.E., G.L.M., N.J.B., C.L.L.); and Department of Pharmacology, New York Medical College, Valhalla (M.L.-S.)
| | - Nancy J Brown
- From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.E., G.L.M., N.J.B., C.L.L.); and Department of Pharmacology, New York Medical College, Valhalla (M.L.-S.)
| | - Michal Laniado-Schwartzman
- From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.E., G.L.M., N.J.B., C.L.L.); and Department of Pharmacology, New York Medical College, Valhalla (M.L.-S.)
| | - Cheryl L Laffer
- From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.E., G.L.M., N.J.B., C.L.L.); and Department of Pharmacology, New York Medical College, Valhalla (M.L.-S.)
| |
Collapse
|
|
26
|
Abstract
Hypertension is the leading risk factor for heart disease and stroke, and is estimated to cause 9.4 million deaths globally every year. The pathogenesis of hypertension is complex, but lifestyle factors such as diet are important contributors to the disease. High dietary intake of fruit and vegetables is associated with reduced blood pressure and lower cardiovascular mortality. A critical relationship between dietary intake and the composition of the gut microbiota has been described in the literature, and a growing body of evidence supports the role of the gut microbiota in the regulation of blood pressure. In this Review, we describe the mechanisms by which the gut microbiota and its metabolites, including short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides, act on downstream cellular targets to prevent or contribute to the pathogenesis of hypertension. These effects have a direct influence on tissues such as the kidney, the endothelium, and the heart. Finally, we consider the role of the gut microbiota in resistant hypertension, the possible intergenerational effect of the gut microbiota on blood pressure regulation, and the promising therapeutic potential of gut microbiota modification to improve health and prevent disease.
Collapse
Affiliation(s)
- Francine Z Marques
- Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.,Department of Pharmacology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton Victoria 3800, Australia
| | - Charles R Mackay
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, 23 Innovation Walk, Clayton, Victoria 3800, Australia
| | - David M Kaye
- Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.,Heart Centre, Alfred Hospital, Philip Block, Level 3, 55 Commercial Road, Melbourne, Victoria 3004, Australia.,Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, 99 Commercial Road, Melbourne, Victoria 3004, Australia
| |
Collapse
|
|
27
|
Fan F, Roman RJ. Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology. J Am Soc Nephrol 2017; 28:2845-2855. [PMID: 28701518 DOI: 10.1681/asn.2017030252] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have essential roles in the regulation of renal tubular and vascular function. Sequence variants in the genes that produce 20-hydroxyeicosatetraenoic acid are associated with hypertension in humans, whereas the evidence supporting a role for variants in the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in animal models suggest that changes in the production of cytochrome P450 eicosanoids alter BP. However, the mechanisms involved remain controversial, especially for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natriuretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory properties that oppose the development of hypertension and CKD; 20-hydroxyeicosatetraenoic acid levels are elevated after renal ischemia and may protect against injury. Levels of this eicosanoid are also elevated in polycystic kidney disease and may contribute to cyst formation. Our review summarizes the emerging evidence that cytochrome P450 eicosanoids have a role in the pathogenesis of hypertension, polycystic kidney disease, AKI, and CKD.
Collapse
Affiliation(s)
- Fan Fan
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Richard J Roman
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| |
Collapse
|
|
28
|
Hu J, Geyer A, Dziumbla S, Awwad K, Zeldin DC, Schunck WH, Popp R, Frömel T, Fleming I. Role of Müller cell cytochrome P450 2c44 in murine retinal angiogenesis. Prostaglandins Other Lipid Mediat 2017; 133:93-102. [PMID: 28442442 DOI: 10.1016/j.prostaglandins.2017.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 04/17/2017] [Accepted: 04/19/2017] [Indexed: 12/11/2022]
Abstract
Polyunsaturated fatty acids (PUFA) and their cytochrome P450 (CYP450) metabolites have been linked to angiogenesis and vessel homeostasis. However, the role of individual CYP isoforms and their endogenous metabolites in those processes are not clear. Here, we focused on the role of Cyp2c44 in postnatal retinal angiogenesis and report that Cyp2c44 is highly expressed in Müller glial cells in the retina. The constitutive as well as inducible postnatal genetic deletion of Cyp2c44 resulted in an increased vessel network density without affecting vessel radial expansion during the first postnatal week. This phenotype was associated with an increased endothelial cell proliferation and attenuated Notch signaling. LC-MS/MS analyses revealed that levels of hydroxydocosahexaenoic acids (HDHA), i.e., 10-, 17- and 20-HDHA were significantly elevated in retinas from 5day old Cyp2c44-/- mice compared to their wild-type littermates. Enzymatic activity assays revealed that HDHAs were potential substrates for Cyp2c44 which could account for the increased levels of HDHAs in retinas from Cyp2c44-/- mice. These data indicate that Cyp2c44 is expressed in the murine retina and, like the soluble epoxide hydrolase, is expressed in Müller glia cells. The enhanced endothelial cell proliferation and Notch inhibition seen in retinas from Cyp2c44-deficient mice indicate a role for Cyp2c44-derived lipid mediators in physiological angiogenesis.
Collapse
Affiliation(s)
- Jiong Hu
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany; German Center of Cardiovascular Research (DZHK) Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Alexandra Geyer
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany
| | - Sarah Dziumbla
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany; German Center of Cardiovascular Research (DZHK) Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Khader Awwad
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany
| | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Wolf-Hagen Schunck
- Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, 13092 Berlin, Germany
| | - Rüdiger Popp
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany
| | - Timo Frömel
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany; German Center of Cardiovascular Research (DZHK) Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, D-60596, Germany; German Center of Cardiovascular Research (DZHK) Partner site Rhein-Main, Frankfurt am Main, Germany.
| |
Collapse
|
|
29
|
Marques FZ, Nelson E, Chu PY, Horlock D, Fiedler A, Ziemann M, Tan JK, Kuruppu S, Rajapakse NW, El-Osta A, Mackay CR, Kaye DM. High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice. Circulation 2017; 135:964-977. [DOI: 10.1161/circulationaha.116.024545] [Citation(s) in RCA: 719] [Impact Index Per Article: 89.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/29/2016] [Indexed: 01/11/2023]
Abstract
Background:
Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here, we evaluated the effect of a high-fiber diet and supplementation with the short-chain fatty acid acetate on the gut microbiota and the prevention of cardiovascular disease.
Methods:
Gut microbiome, cardiorenal structure/function, and blood pressure were examined in sham and mineralocorticoid excess–treated mice with a control diet, high-fiber diet, or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets.
Results:
We found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria independently of mineralocorticoid excess. Both fiber and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of
Bacteroides acidifaciens
. Compared with mineralocorticoid-excess mice fed a control diet, both high-fiber diet and acetate supplementation significantly reduced systolic and diastolic blood pressures, cardiac fibrosis, and left ventricular hypertrophy. Acetate had similar effects and markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fiber and acetate were accompanied by the downregulation of cardiac and renal
Egr1
, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation. We also observed the upregulation of a network of genes involved in circadian rhythm in both tissues and downregulation of the renin-angiotensin system in the kidney and mitogen-activated protein kinase signaling in the heart.
Conclusions:
A diet high in fiber led to changes in the gut microbiota that played a protective role in the development of cardiovascular disease. The favorable effects of fiber may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.
Collapse
Affiliation(s)
- Francine Z. Marques
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Erin Nelson
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Po-Yin Chu
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Duncan Horlock
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - April Fiedler
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Mark Ziemann
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Jian K. Tan
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Sanjaya Kuruppu
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Niwanthi W. Rajapakse
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Assam El-Osta
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - Charles R. Mackay
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| | - David M. Kaye
- From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash
| |
Collapse
|
|
30
|
Sadeghi M, Roohafza H, Pourmoghaddas M, Behnamfar O, Pourmoghaddas Z, Heidari E, Mahjoor Z, Mousavi M, Bahonar A, Sarrafzadegan N. How far cardio metabolic and psychological factors affect salt sensitivity in normotensive adult population? World J Cardiol 2017; 9:47-54. [PMID: 28163836 PMCID: PMC5253194 DOI: 10.4330/wjc.v9.i1.47] [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: 07/21/2016] [Revised: 10/08/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the prevalence of salt sensitivity and the impact of cardiometabolic and psychological characteristics on salt sensitivity in normotensive population.
METHODS Of all participants, anthropometric measurements and fasting venous blood samples were collected, and study questionnaires were completed. Salt Sensitivity was defined based on the difference in mean arterial pressure with infusion of 2 L of normal saline followed by a low sodium diet and administration of three doses of oral furosemide the day after.
RESULTS Of 131 participants, 56 (42.7%) were diagnosed with salt sensitivity. Crude and age and sex adjusted regression analysis showed that low-density lipoprotein cholesterol and depression were positively associated with salt sensitivity (OR = 1.02, 95%CI: 1.01-1.04 and OR = 1.15, 95%CI: 1.00-1.34, respectively).
CONCLUSION The high prevalence of salt sensitivity and its significant relation with prevalent risk factors necessitates considering its reduction actions at the population level and the need for further research.
Collapse
|
|
31
|
Okemoto K, Maekawa K, Tajima Y, Tohkin M, Saito Y. Cross-Classification of Human Urinary Lipidome by Sex, Age, and Body Mass Index. PLoS One 2016; 11:e0168188. [PMID: 27973561 PMCID: PMC5156423 DOI: 10.1371/journal.pone.0168188] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 11/29/2016] [Indexed: 12/17/2022] Open
Abstract
Technological advancements in past decades have led to the development of integrative analytical approaches to lipidomics, such as liquid chromatography-mass spectrometry (LC/MS), and information about biogenic lipids is rapidly accumulating. Although several cohort-based studies have been conducted on the composition of urinary lipidome, the data on urinary lipids cross-classified by sex, age, and body mass index (BMI) are insufficient to screen for various abnormalities. To promote the development of urinary lipid metabolome-based diagnostic assay, we analyzed 60 urine samples from healthy white adults (young (c.a., 30 years) and old (c.a., 60 years) men/women) using LC/MS. Women had a higher urinary concentration of omega-3 12-lipoxygenase (LOX)-generated oxylipins with anti-inflammatory activity compared to men. In addition, young women showed increased abundance of poly-unsaturated fatty acids (PUFAs) and cytochrome P450 (P450)-produced oxylipins with anti-hypertensive activity compared with young men, whereas elderly women exhibited higher concentration of 5-LOX-generated anti-inflammatory oxylipins than elderly men. There were no significant differences in urinary oxylipin levels between young and old subjects or between subjects with low and high BMI. Our findings suggest that sex, but neither ages nor BMI could be a confounding factor for measuring the composition of urinary lipid metabolites in the healthy population. The information showed contribute to the development of reliable biomarker findings from urine.
Collapse
Affiliation(s)
- Kazuo Okemoto
- Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, Japan
- Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Keiko Maekawa
- Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, Japan
| | - Yoko Tajima
- Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, Japan
- Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Masahiro Tohkin
- Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Yoshiro Saito
- Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, Japan
| |
Collapse
|
|
32
|
Elijovich F, Weinberger MH, Anderson CAM, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL. Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association. Hypertension 2016; 68:e7-e46. [PMID: 27443572 DOI: 10.1161/hyp.0000000000000047] [Citation(s) in RCA: 361] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
|
|
33
|
Savas Ü, Wei S, Hsu MH, Falck JR, Guengerich FP, Capdevila JH, Johnson EF. 20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice: NORMALIZATION OF BLOOD PRESSURE BY SODIUM RESTRICTION, HYDROCHLOROTHIAZIDE, OR BLOCKADE OF THE TYPE 1 ANGIOTENSIN II RECEPTOR. J Biol Chem 2016; 291:16904-19. [PMID: 27298316 DOI: 10.1074/jbc.m116.732297] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Indexed: 11/06/2022] Open
Abstract
Male and female homozygous 129/Sv mice carrying four copies of the human cytochrome P450 4A11 gene (CYP4A11) under control of its native promoter (B-129/Sv-4A11(+/+)) develop hypertension (142 ± 8 versus 113 ± 7 mm Hg systolic blood pressure (BP)), and exhibit increased 20-hydroxyeicosatetraenoic acid (20-HETE) in kidney and urine. The hypertension is reversible by a low-sodium diet and by the CYP4A inhibitor HET0016. B-129/Sv-4A11(+/+) mice display an 18% increase of plasma potassium (p < 0.02), but plasma aldosterone, angiotensin II (ANGII), and renin activities are unchanged. This phenotype resembles human genetic disorders with elevated activity of the sodium chloride co-transporter (NCC) and, accordingly, NCC abundance is increased by 50% in transgenic mice, and NCC levels are normalized by HET0016. ANGII is known to increase NCC abundance, and renal mRNA levels of its precursor angiotensinogen are increased 2-fold in B-129/Sv-4A11(+/+), and blockade of the ANGII receptor type 1 with losartan normalizes BP. A pro-hypertensive role for 20-HETE was implicated by normalization of BP and reversal of renal angiotensin mRNA increases by administration of the 20-HETE antagonists 2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)acetate or (S)-2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)succinate. SGK1 expression is also increased in B-129/Sv-4A11(+/+) mice and paralleled increases seen for NCC. Losartan, HET0016, and 20-HETE antagonists each normalized SGK1 mRNA expression. These results point to a potential 20-HETE dependence of intrarenal angiotensinogen production and ANGII receptor type 1 activation that are associated with increases in NCC and SGK1 and identify elevated P450 4A11 activity and 20-HETE as potential risk factors for salt-sensitive human hypertension by perturbation of the renal renin-angiotensin axis.
Collapse
Affiliation(s)
- Üzen Savas
- From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
| | | | - Mei-Hui Hsu
- From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
| | - John R Falck
- the Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - F Peter Guengerich
- Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and
| | | | - Eric F Johnson
- From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,
| |
Collapse
|
|
34
|
Bai JJ, Tan CD, Chow BKC. Secretin, at the hub of water-salt homeostasis. Am J Physiol Renal Physiol 2016; 312:F852-F860. [PMID: 27279485 DOI: 10.1152/ajprenal.00191.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/01/2016] [Indexed: 01/13/2023] Open
Abstract
Water and salt metabolism are tightly regulated processes. Maintaining this milieu intérieur within narrow limits is critical for normal physiological processes to take place. Disturbances to this balance can result in disease and even death. Some of the better-characterized regulators of water and salt homeostasis include angiotensin II, aldosterone, arginine vasopressin, and oxytocin. Although secretin (SCT) was first described >100 years ago, little is known about the role of this classic gastrointestinal hormone in the maintenance of water-salt homeostasis. In recent years, increasing body of evidence suggested that SCT and its receptor play important roles in the central nervous system and kidney to ensure that the mammalian extracellular fluid osmolarity is kept within a healthy range. In this review, we focus on recent advances in our understanding of the molecular, cellular, and network mechanisms by which SCT and its receptor mediate the control of osmotic homeostasis. Implications of hormonal cross talk and receptor-receptor interaction are highlighted.
Collapse
Affiliation(s)
- Jenny Juan Bai
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Chong Da Tan
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Billy K C Chow
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
35
|
The role of 20-HETE in cardiovascular diseases and its risk factors. Prostaglandins Other Lipid Mediat 2016; 125:108-17. [PMID: 27287720 DOI: 10.1016/j.prostaglandins.2016.05.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/20/2016] [Accepted: 05/31/2016] [Indexed: 01/03/2023]
Abstract
Arachidonic acid (AA) is metabolized in mammals by enzymes of the CYP4A and 4F families to 20-hydroxyeicosatetraeonic acid (20-HETE) which plays an important role in the regulation of renal function, vascular tone and arterial pressure. In the vasculature, 20-HETE is a potent vasoconstrictor, the up-regulation of which contributes to inflammation, oxidative stress, endothelial dysfunction and an increase in peripheral vascular resistance in models of obesity, diabetes, ischemia/reperfusion, and vascular oxidative stress. Recent studies have established a role for 20-HETE in normal and pathological angiogenic conditions. We discuss in this review the synthesis of 20-HETE and how it and various autacoids, especially the renin-angiotensin system, interact to promote hypertension, vasoconstriction, and vascular dysfunction. In addition, we examine the molecular mechanisms through which 20-HETE induces these actions and the clinical implication of inhibiting 20-HETE production and activity.
Collapse
|
|
36
|
Imig JD. Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2016; 77:105-41. [PMID: 27451096 DOI: 10.1016/bs.apha.2016.04.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Endothelial and vascular smooth cells generate cytochrome P450 (CYP) arachidonic acid metabolites that can impact endothelial cell function and vascular homeostasis. The objective of this review is to focus on the physiology and pharmacology of endothelial CYP metabolites. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP hydroxylases. Advances in CYP enzymes, EETs, and 20-HETE by pharmacological and genetic means have led to a more complete understanding of how these eicosanoids impact on endothelial cell function. Endothelial-derived EETs were initially described as endothelial-derived hyperpolarizing factors. It is now well recognized that EETs importantly contribute to numerous endothelial cell functions. On the other hand, 20-HETE is the predominant CYP hydroxylase synthesized by vascular smooth muscle cells. Like EETs, 20-HETE acts on endothelial cells and impacts importantly on endothelial and vascular function. An important aspect for EETs and 20-HETE endothelial actions is their interactions with hormonal and paracrine factors. These include interactions with the renin-angiotensin system, adrenergic system, puringeric system, and endothelin. Alterations in CYP enzymes, 20-HETE, or EETs contribute to endothelial dysfunction and cardiovascular diseases such as ischemic injury, hypertension, and atherosclerosis. Recent advances have led to the development of potential therapeutics that target CYP enzymes, 20-HETE, or EETs. Thus, future investigation is required to obtain a more complete understanding of how CYP enzymes, 20-HETE, and EETs regulate endothelial cell function.
Collapse
Affiliation(s)
- J D Imig
- Medical College of Wisconsin, Milwaukee, WI, United States.
| |
Collapse
|
|
37
|
Fu F, Chen F, Li R, Zhang Y, Pan M, Li D, Liao C. Prenatal diagnosis of fetal multicystic dysplastic kidney via high-resolution whole-genome array. Nephrol Dial Transplant 2016; 31:1693-8. [PMID: 26932690 DOI: 10.1093/ndt/gfv465] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 12/25/2015] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Women with fetal multicystic dysplastic kidneys (MCDK) are commonly referred for genetic counseling, for which identification of the correct etiology is a prerequisite. METHODS A total of 72 women with fetal MCDK at Guangzhou Women and Children's Medical Center were examined via invasive prenatal diagnosis from May 2010 to June 2015. Standard karyotyping analysis was provided to all fetuses, and chromosomal microarray with Affymetrix CytoSan HD arrays was offered to cases whose DNA samples were available. RESULTS Abnormal karyotypes were detected in 3 of 72 (4.17%) fetuses. Of the 69 (95.8%, 69/72) fetuses with normal karyotypes, 30 (42%, 30/69) underwent chromosome microarray analysis (CMA) testing. The CMA identified pathogenic copy number variations in five fetuses, leading to a pathogenic detection rate of 16.7% (5/30). Well-known microdeletion or microduplication syndromes including renal cysts and diabetes (RCAD) syndrome and Williams-Beuren syndrome (WBS) were identified in three cases. Moreover, four chromosomal imbalanced regions were also identified in our MCDK fetuses: 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK. The proportions of variants of unknown significance before and after parental analysis were 13.3% (4/30) and 3.3% (1/30), respectively. CONCLUSIONS In the present study, the frequency of chromosomal abnormalities in MCDK fetuses was 4.17% and all rearrangements were imbalanced aberrations. CMA was able to increase the pathogenic detection rate to 16.7% in MCDK fetuses with normal karyotype. Critical regions for RCAD syndrome, WBS and copy number variants of 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication were associated with fetal MCDK. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK.
Collapse
Affiliation(s)
- Fang Fu
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Feifei Chen
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ru Li
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yongling Zhang
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Min Pan
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Dongzhi Li
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Can Liao
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
38
|
Abstract
Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function.
Collapse
Affiliation(s)
- John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Md Abdul Hye Khan
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| |
Collapse
|
|
39
|
Carrisoza-Gaytan R, Carattino MD, Kleyman TR, Satlin LM. An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron. Am J Physiol Cell Physiol 2015; 310:C243-59. [PMID: 26632600 DOI: 10.1152/ajpcell.00328.2015] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Flow-induced K secretion (FIKS) in the aldosterone-sensitive distal nephron (ASDN) is mediated by large-conductance, Ca(2+)/stretch-activated BK channels composed of pore-forming α-subunits (BKα) and accessory β-subunits. This channel also plays a critical role in the renal adaptation to dietary K loading. Within the ASDN, the cortical collecting duct (CCD) is a major site for the final renal regulation of K homeostasis. Principal cells in the ASDN possess a single apical cilium whereas the surfaces of adjacent intercalated cells, devoid of cilia, are decorated with abundant microvilli and microplicae. Increases in tubular (urinary) flow rate, induced by volume expansion, diuretics, or a high K diet, subject CCD cells to hydrodynamic forces (fluid shear stress, circumferential stretch, and drag/torque on apical cilia and presumably microvilli/microplicae) that are transduced into increases in principal (PC) and intercalated (IC) cell cytoplasmic Ca(2+) concentration that activate apical voltage-, stretch- and Ca(2+)-activated BK channels, which mediate FIKS. This review summarizes studies by ourselves and others that have led to the evolving picture that the BK channel is localized in a macromolecular complex at the apical membrane, composed of mechanosensitive apical Ca(2+) channels and a variety of kinases/phosphatases as well as other signaling molecules anchored to the cytoskeleton, and that an increase in tubular fluid flow rate leads to IC- and PC-specific responses determined, in large part, by the cell-specific composition of the BK channels.
Collapse
Affiliation(s)
| | - Marcelo D Carattino
- Renal-Electrolyte Division, Department of Medicine, Pittsburgh, Pennsylvania
| | - Thomas R Kleyman
- Renal-Electrolyte Division, Department of Medicine, Pittsburgh, Pennsylvania
| | - Lisa M Satlin
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York; and
| |
Collapse
|
|
40
|
Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel‐Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 2015; 14:1034-44. [PMID: 26172407 PMCID: PMC4693458 DOI: 10.1111/acel.12372] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2015] [Indexed: 12/24/2022] Open
Abstract
Aging is associated with marked deficiency in circulating IGF‐1, which has been shown to contribute to age‐related cognitive decline. Impairment of moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age‐related cognitive impairment. To establish the link between IGF‐1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF‐1 deficiency (Igf1f/f‐TBG‐Cre‐AAV8) and accelerated vascular aging. We found that IGF‐1‐deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal‐dependent spatial memory test, mimicking the aging phenotype. IGF‐1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF‐1 deficiency also impaired glutamate‐mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF‐1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.
Collapse
Affiliation(s)
- Peter Toth
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- Department of Neurosurgery and Szentagothai Research Center Medical School University of Pecs Pecs 7624 Hungary
| | - Stefano Tarantini
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- Department of Physiology University of Oklahoma Health Sciences Center 940 S.L. Young Blvd. Rm. 653 Oklahoma City 73104OK USA
| | - Nicole M. Ashpole
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
| | - Zsuzsanna Tucsek
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
| | - Ginger L. Milne
- Division of Clinical Pharmacology Vanderbilt University Medical Center D‐3100 Medical Center North Nashville TN USA
| | - Noa M. Valcarcel‐Ares
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
| | - Akos Menyhart
- Department of Medical Physics and Informatics Faculty of Medicine and Faculty of Science and Informatics University of Szeged Szeged 6720Hungary
| | - Eszter Farkas
- Department of Medical Physics and Informatics Faculty of Medicine and Faculty of Science and Informatics University of Szeged Szeged 6720Hungary
| | - William E. Sonntag
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- The Peggy and Charles Stephenson Cancer Center University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
| | - Anna Csiszar
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- Department of Neurosurgery and Szentagothai Research Center Medical School University of Pecs Pecs 7624 Hungary
- Department of Physiology University of Oklahoma Health Sciences Center 940 S.L. Young Blvd. Rm. 653 Oklahoma City 73104OK USA
- The Peggy and Charles Stephenson Cancer Center University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
| | - Zoltan Ungvari
- Donald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- Department of Neurosurgery and Szentagothai Research Center Medical School University of Pecs Pecs 7624 Hungary
- Department of Physiology University of Oklahoma Health Sciences Center 940 S.L. Young Blvd. Rm. 653 Oklahoma City 73104OK USA
- The Peggy and Charles Stephenson Cancer Center University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- Department of Pulmonology 1125 Budapest, Diós árok 1/c Semmelweis University Budapest Hungary
| |
Collapse
|
|
41
|
Garcia V, Joseph G, Shkolnik B, Ding Y, Zhang FF, Gotlinger K, Falck JR, Dakarapu R, Capdevila JH, Bernstein KE, Schwartzman ML. Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 2015; 309:R71-8. [PMID: 25924878 PMCID: PMC4491537 DOI: 10.1152/ajpregu.00039.2015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 04/18/2015] [Indexed: 01/13/2023]
Abstract
Increased vascular 20-HETE is associated with hypertension and activation of the renin-angiotensin system (RAS) through induction of vascular angiotensin-converting enzyme (ACE) expression. Cyp4a12tg mice, whose Cyp4a12-20-HETE synthase expression is under the control of a tetracycline (doxycycline, DOX) promoter, were used to assess the contribution of ACE/RAS to microvascular remodeling in 20-HETE-dependent hypertension. Treatment of Cyp4a12tg mice with DOX increased systolic blood pressure (SBP; 136 ± 2 vs. 102 ± 1 mmHg; P < 0.05), and this increase was prevented by administration of 20-HEDGE, lisinopril, or losartan. DOX-induced hypertension was associated with microvascular dysfunction and remodeling of preglomerular microvessels, which was prevented by 20-HEDGE, a 20-HETE antagonist, yet only lessened, but not prevented, by lisinopril or losartan. In ACE 3/3 mice, which lack vascular endothelial ACE, administration of 5α-dihydrotestosterone (DHT), a known inducer of 20-HETE production, increased SBP; however, the increase was about 50% of that in wild-type (WT) mice (151 ± 1 vs. 126 ± 1 mmHg). Losartan and 20-HEDGE prevented the DHT-induced increase in SBP in WT and ACE 3/3 mice. DHT treatment increased 20-HETE production and microvascular remodeling in WT and ACE 3/3 mice; however, remodeling was attenuated in the ACE 3/3 mice as opposed to WT mice (15.83 ± 1.11 vs. 22.17 ± 0.92 μm; P < 0.05). 20-HEDGE prevented microvascular remodeling in WT and ACE 3/3 mice, while losartan had no effect on microvascular remodeling in ACE 3/3. Taken together, these results suggest that RAS contributes to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE-driven microvascular remodeling independent of blood pressure elevation does not fully rely on ACE activity in the vascular endothelium.
Collapse
Affiliation(s)
- Victor Garcia
- Department of Pharmacology, New York Medical College, Valhalla, New York;
| | - Gregory Joseph
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Brian Shkolnik
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Yan Ding
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Frank Fan Zhang
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | | | - John R Falck
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Rambabu Dakarapu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jorge H Capdevila
- Departments of Medicine and Biochemistry, Vanderbilt University, Nashville, Tennessee; and
| | - Kenneth E Bernstein
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | | |
Collapse
|
|
42
|
Nyagode BA, Williams IR, Morgan ET. Altered inflammatory responses to Citrobacter rodentium infection, but not bacterial lipopolysaccharide, in mice lacking the Cyp4a10 or Cyp4a14 genes. Inflammation 2015; 37:893-907. [PMID: 24413902 DOI: 10.1007/s10753-013-9809-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Murine hepatic Cyp4a mRNAs are markedly downregulated during inflammation. Here, we investigated the roles of Cyp4a10 and Cyp4a14 in the response to infection with C. rodentium. Absence of either Cyp4a gene attenuated or abrogated the changes in spleen weight, colon crypt length, hepatic cytokine, and acute phase protein mRNAs, and serum acute phase proteins and cytokines caused by infection. Cyp4a10(-/-) mice on a low-salt diet had a similar hepatic acute phase response as those mice on a high-salt diet, suggesting that hypertension associated with this genotype is not the cause of their altered inflammatory response. In contrast, wild-type, Cyp4a10(-/-), and Cyp4a14(-/-) mice showed similar responses to injected LPS. These results implicate Cyp4a10 and Cyp4a14 in the regulation of the host inflammatory response to enteropathogenic bacterial infection but not to acute aseptic inflammation. Understanding the mechanism of this role may lead to novel therapeutic approaches in some inflammatory diseases.
Collapse
Affiliation(s)
- Beatrice A Nyagode
- Department of Pharmacology, Emory University School of Medicine, 5119 Rollins Research Center, 1510 Clifton Road, Atlanta, GA, 30322, USA
| | | | | |
Collapse
|
|
43
|
Capdevila JH, Wang W, Falck JR. Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance. Prostaglandins Other Lipid Mediat 2015; 120:40-9. [PMID: 25986599 DOI: 10.1016/j.prostaglandins.2015.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 04/19/2015] [Accepted: 05/06/2015] [Indexed: 12/22/2022]
Abstract
Studies with rat genetic models of hypertension pointed to roles for the CYP2C and CYP4A arachidonic acid epoxygenases and ω-hydroxylases in tubular transport, hemodynamics, and blood pressure control. Further progress in defining their physiological functions and significance to human hypertension requires conclusive identifications of the relevant genes and proteins. Here we discuss unequivocal evidence of roles for the murine Cyp4a14, Cyp4a10, and Cyp2c44 genes in the pathophysiology of hypertension by showing that: (a) Cyp4a14(-/-) mice develop sexually dimorphic hypertension associated with renal vasoconstriction, and up-regulated expression of Cyp4a12a and pro-hypertensive 20-hydroxyeicosatetraenoic acid (20-HETE) levels, and b) Cyp4a10(-/-) and Cyp2c44(-/-) mice develop salt sensitive hypertension linked to downregulation or lack of the Cyp2c44 epoxygenase, reductions in anti-hypertensive epoxyeicosatrienoic acids (EETs), and increases in distal sodium reabsorption. Based on these studies, the human CYP4A11 and CYPs 2C8 and 2C9 genes and their products are identified as potential candidates for studies of the molecular basis of human hypertension.
Collapse
Affiliation(s)
- Jorge H Capdevila
- Department of Medicine, Vanderbilt University Medical School, Nashville, TN 37232, USA.
| | - Wenhui Wang
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
| | - John R Falck
- Department of Biochemistry, UT Southwestern Medical Center , Dallas, TX 75390, USA.
| |
Collapse
|
|
44
|
Wen D, Yuan Y, Warner PC, Wang B, Cornelius RJ, Wang-France J, Li H, Boettger T, Sansom SC. Increased Epithelial Sodium Channel Activity Contributes to Hypertension Caused by Na+-HCO3- Cotransporter Electrogenic 2 Deficiency. Hypertension 2015; 66:68-74. [PMID: 25941340 DOI: 10.1161/hypertensionaha.115.05394] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 04/14/2015] [Indexed: 11/16/2022]
Abstract
The gene SLC4A5 encodes the Na(+)-HCO3 (-) cotransporter electrogenic 2, which is located in the distal nephron. Genetically deleting Na(+)-HCO3 (-) cotransporter electrogenic 2 (knockout) causes Na(+)-retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether overactive epithelial Na(+) channels (ENaC) or the Na(+)-Cl(-) cotransporter causes the Na(+) retention and hypertension in knockout. In untreated mice, the mean arterial pressure was higher in knockout, compared with wild-type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide, an inhibitor of Na(+)-Cl(-) cotransporter, decreased mean arterial pressure in WT, but not knockout. Western blots showed that quantity of plasmalemmal full-length ENaC-α was significantly higher in knockout than in WT. Amiloride treatment caused a 2-fold greater increase in Na(+) excretion in knockout, compared with WT. In knockout, but not WT, amiloride treatment decreased plasma [Na(+)] and urinary K(+) excretion, but increased hematocrit and plasma [K(+)] significantly. Micropuncture with microelectrodes showed that the [K(+)] was significantly higher and the transepithelial potential (Vte) was significantly lower in the late distal tubule of the knockout compared with WT. The reduced Vte in knockout was amiloride sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na(+) reabsorption in this segment. These results show that, in the absence of Na(+)-HCO3 (-) cotransporter electrogenic 2 in the late distal tubule, acid-loaded mice exhibit disinhibition of ENaC-mediated Na(+) reabsorption, which results in Na(+) retention, K(+) wasting, and hypertension.
Collapse
Affiliation(s)
- Donghai Wen
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Yang Yuan
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Paige C Warner
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Bangchen Wang
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Ryan J Cornelius
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Jun Wang-France
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Huaqing Li
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Thomas Boettger
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.)
| | - Steven C Sansom
- From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.).
| |
Collapse
|
|
45
|
Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC. Vascular actions of 20-HETE. Prostaglandins Other Lipid Mediat 2015; 120:9-16. [PMID: 25813407 DOI: 10.1016/j.prostaglandins.2015.03.002] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/27/2015] [Accepted: 03/04/2015] [Indexed: 12/12/2022]
Abstract
20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid that exhibits a myriad of biological effects in the vascular system. This review discusses the current knowledge related to the effects of 20-HETE on vascular reactivity, activation, and remodeling, as well as its role in vascular inflammation and angiogenesis. The information explaining how 20-HETE and the renin-angiotensin system interact to promote hypertension, vasoconstriction, and vascular dysfunction is summarized in this article. 20-HETE enhances vascular inflammation and injury in models of diabetes, ischemia/reperfusion, and cerebrovascular oxidative stress. Recent studies also established a role for 20-HETE in normal and pathological angiogenesis conditions. This review will also discuss the molecular mechanisms through which 20-HETE induces these vascular actions. Potential additional studies are suggested to address shortcomings in the current knowledge of 20-HETE in the vascular system.
Collapse
Affiliation(s)
- Samantha L Hoopes
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Victor Garcia
- Department of Pharmacology, New York Medical College, Valhalla, NY, USA
| | - Matthew L Edin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | | | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| |
Collapse
|
|
46
|
Imig JD. Epoxyeicosatrienoic acids, hypertension, and kidney injury. Hypertension 2015; 65:476-82. [PMID: 25583156 PMCID: PMC4326585 DOI: 10.1161/hypertensionaha.114.03585] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 12/09/2014] [Indexed: 12/25/2022]
Affiliation(s)
- John D Imig
- From the Department of Pharmacology and Toxicology, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee.
| |
Collapse
|
|
47
|
Marumo T, Yagi S, Kawarazaki W, Nishimoto M, Ayuzawa N, Watanabe A, Ueda K, Hirahashi J, Hishikawa K, Sakurai H, Shiota K, Fujita T. Diabetes Induces Aberrant DNA Methylation in the Proximal Tubules of the Kidney. J Am Soc Nephrol 2015; 26:2388-97. [PMID: 25653098 DOI: 10.1681/asn.2014070665] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/26/2014] [Indexed: 01/07/2023] Open
Abstract
Epigenetic mechanisms may underlie the progression of diabetic kidney disease. Because the kidney is a heterogeneous organ with different cell types, we investigated DNA methylation status of the kidney in a cell type-specific manner. We first identified genes specifically demethylated in the normal proximal tubules obtained from control db/m mice, and next delineated the candidate disease-modifying genes bearing aberrant DNA methylation induced by diabetes using db/db mice. Genes involved in glucose metabolism, including Sglt2, Pck1, and G6pc, were selectively hypomethylated in the proximal tubules in control mice. Hnf4a, a transcription factor regulating transporters for reabsorption, was also selectively demethylated. In diabetic mice, aberrant hypomethylation of Agt, Abcc4, Cyp4a10, Glut5, and Met and hypermethylation of Kif20b, Cldn18, and Slco1a1 were observed. Time-dependent demethylation of Agt, a marker of diabetic kidney disease, was accompanied by histone modification changes. Furthermore, inhibition of DNA methyltransferase or histone deacetylase increased Agt mRNA in cultured human proximal tubular cells. Aberrant DNA methylation and concomitant changes in histone modifications and mRNA expression in the diabetic kidney were resistant to antidiabetic treatment with pioglitazone. These results suggest that an epigenetic switch involving aberrant DNA methylation causes persistent mRNA expression of select genes that may lead to phenotype changes of the proximal tubules in diabetic kidney disease.
Collapse
Affiliation(s)
- Takeshi Marumo
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, CREST, Japan Science and Technology Agency, Tokyo, Japan
| | - Shintaro Yagi
- Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, and
| | - Wakako Kawarazaki
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology
| | - Mitsuhiro Nishimoto
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology
| | - Nobuhiro Ayuzawa
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology
| | - Atsushi Watanabe
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology
| | - Kohei Ueda
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology
| | - Junichi Hirahashi
- Apheresis and Dialysis Center, School of Medicine, Keio University, Tokyo, Japan; and
| | - Keiichi Hishikawa
- Department of Advanced Nephrology and Regenerative Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Sakurai
- Department of Pharmacology, School of Medicine, Kyorin University, Tokyo, Japan
| | - Kunio Shiota
- Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, and
| | - Toshiro Fujita
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, CREST, Japan Science and Technology Agency, Tokyo, Japan;
| |
Collapse
|
|
48
|
Abstract
PURPOSE OF REVIEW Cytochrome (CYP) P450 metabolites of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) contribute to the regulation of renal tubular and vascular function. This review highlights the results of the recent genetic studies in humans and rodent models, indicating that these eicosanoids participate in the control of blood pressure (BP), chronic kidney disease (CKD), renal ischemia-reperfusion injury (IRI) and polycystic kidney disease (PKD). RECENT FINDINGS Endogenous 20-HETE has been reported to play an essential role in the myogenic and tubuloglomerular feedback responses in the afferent arteriole, and a deficiency of 20-HETE contributes to the development of hypertension and renal injury in Dahl S rats. Mutations in CYP4A11 and CYP4F2 have been linked to elevated BP in humans. EETs have been shown to regulate epithelial sodium channel in the collecting duct, lower BP and have renoprotective properties. 20-HETE also opposes the development of CKD and IRI, and may play a role in PKD. SUMMARY These studies indicate that CYP P450 metabolites of arachidonic acid play an important role in the control of BP, CKD, AKI and PKD. Drugs targeting these pathways could be useful in the treatment of IRI and CKD.
Collapse
Affiliation(s)
- Fan Fan
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | | | | |
Collapse
|
|
49
|
Hye Khan MA, Pavlov TS, Christain SV, Neckář J, Staruschenko A, Gauthier KM, Capdevila JH, Falck JR, Campbell WB, Imig JD. Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 2014; 127:463-74. [PMID: 24707975 PMCID: PMC4167712 DOI: 10.1042/cs20130479] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Epoxyeicosatrienoic acids (EETs) contribute to haemodynamics, electrolyte homoeostasis and blood pressure regulation, leading to the concept that EETs can be therapeutically targeted for hypertension. In the present study, multiple structural EET analogues were synthesized based on the EET pharmacophore and vasodilator structure-activity studies. Four EET analogues with 91-119% vasodilatory activity in the isolated bovine coronary artery (EC50: 0.18-1.6 μM) were identified and studied for blood-pressure-lowering in hypertension. Two EET analogues in which the COOH group at carbon 1 of the EET pharmacophore was replaced with either an aspartic acid (EET-A) or a heterocyclic surrogate (EET-X) were administered for 14 days [10 mg/kg per day intraperitoneally (i.p.)]. Both EET-A and EET-X lowered blood pressure in spontaneously hypertensive rats (SHRs) and in angiotensin II (AngII) hypertension. On day 14, the mean arterial pressures in EET analogue-treated AngII-hypertensive and SHRs were 30-50 mmHg (EET-A) and 15-20 mmHg (EET-X) lower than those in vehicle-treated controls. These EET analogues (10 mg/kg per day) were further tested in AngII hypertension by administering orally in drinking water for 14 days and EET-A lowered blood pressure. Additional experiments demonstrated that EET-A inhibits epithelial sodium channel (ENaC) activity in cultured cortical collecting duct cells and reduced renal expression of ENaC subunits in AngII hypertension. In conclusion, we have characterized EET-A as an orally active antihypertensive EET analogue that protects vascular endothelial function and has ENaC inhibitory activity in AngII hypertension.
Collapse
Affiliation(s)
- Md Abdul Hye Khan
- *Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, U.S.A
| | - Tengis S Pavlov
- †Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, U.S.A
| | - Sarah V Christain
- *Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, U.S.A
| | | | | | - Kathryn M Gauthier
- *Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, U.S.A
| | - Jorge H Capdevila
- §Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, U.S.A
| | - John R Falck
- ∥Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, TX, U.S.A
| | | | | |
Collapse
|
|
50
|
Fleming I. The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease. Pharmacol Rev 2014; 66:1106-40. [PMID: 25244930 DOI: 10.1124/pr.113.007781] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
Over the last 20 years, it has become clear that cytochrome P450 (P450) enzymes generate a spectrum of bioactive lipid mediators from endogenous substrates. However, studies focused on the determining biologic activity of the P450 system have focused largely on the metabolites generated by one substrate (i.e., arachidonic acid). However, epoxides and diols derived from other endogenous substrates, such as linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid, may be generated in higher concentrations and may potentially be of more physiologic relevance. Recent studies that used a combination of phenotyping and lipid array analyses revealed that rather than being inactive products, fatty acid diols play important roles in a number of biologic processes including inflammation, angiogenesis, and metabolic regulation. Moreover, inhibitors of the soluble epoxide hydrolase that increase epoxide but decrease diol levels have potential for the treatment of the metabolic syndrome.
Collapse
Affiliation(s)
- Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| |
Collapse
|