Physiology - Research Publications

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    Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical Model
    Curl, CL ; Danes, VR ; Bell, JR ; Raaijmakers, AJA ; Ip, WTK ; Chandramouli, C ; Harding, TW ; Porrello, ER ; Erickson, JR ; Charchar, FJ ; Kompa, AR ; Edgley, AJ ; Crossman, DJ ; Soeller, C ; Mellor, KM ; Kalman, JM ; Harrap, S ; Delbridge, LMD (WILEY, 2018-06-05)
    BACKGROUND: Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. METHODS AND RESULTS: The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca2+ operational levels and markedly increased L-type Ca2+ channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed. CONCLUSIONS: Thus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF-and suggest a basis for new therapeutic strategies.
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    2020 International Society of Hypertension Global Hypertension Practice Guidelines
    Unger, T ; Borghi, C ; Charchar, F ; Khan, NA ; Poulter, NR ; Prabhakaran, D ; Ramirez, A ; Schlaich, M ; Stergiou, GS ; Tomaszewski, M ; Wainford, RD ; Williams, B ; Schutte, AE (LIPPINCOTT WILLIAMS & WILKINS, 2020-06-01)
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    Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
    Morris, AP ; Le, TH ; Wu, H ; Akbarov, A ; van der Most, PJ ; Hemani, G ; Smith, GD ; Mahajan, A ; Gaulton, KJ ; Nadkarni, GN ; Valladares-Salgado, A ; Wacher-Rodarte, N ; Mychaleckyj, JC ; Dueker, ND ; Guo, X ; Hai, Y ; Haessler, J ; Kamatani, Y ; Stilp, AM ; Zhu, G ; Cook, JP ; Arnlov, J ; Blanton, SH ; de Borst, MH ; Bottinger, EP ; Buchanan, TA ; Cechova, S ; Charchar, FJ ; Chu, P-L ; Damman, J ; Eales, J ; Gharavi, AG ; Giedraitis, V ; Heath, AC ; Ipp, E ; Kiryluk, K ; Kramer, HJ ; Kubo, M ; Larsson, A ; Lindgren, CM ; Lu, Y ; Madden, PAF ; Montgomery, GW ; Papanicolaou, GJ ; Raffel, LJ ; Sacco, RL ; Sanchez, E ; Stark, H ; Sundstrom, J ; Taylor, KD ; Xiang, AH ; Zivkovic, A ; Lind, L ; Ingelsson, E ; Martin, NG ; Whitfield, JB ; Cai, J ; Laurie, CC ; Okada, Y ; Matsuda, K ; Kooperberg, C ; Chen, Y-DI ; Rundek, T ; Rich, SS ; Loos, RJF ; Parra, EJ ; Cruz, M ; Rotter, J ; Snieder, H ; Tomaszewski, M ; Humphreys, BD ; Franceschini, N (NATURE PORTFOLIO, 2019-01-03)
    Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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    Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney
    Jiang, X ; Eales, JM ; Scannali, D ; Nazgiewicz, A ; Prestes, P ; Maier, M ; Denniff, M ; Xu, X ; Saluja, S ; Cano-Gamez, E ; Wystrychowski, W ; Szulinska, M ; Antczak, A ; Byars, S ; Skrypnik, D ; Glyda, M ; Krol, R ; Zywiec, J ; Zukowska-Szczechowska, E ; Burrell, LM ; Woolf, AS ; Greenstein, A ; Bogdanski, P ; Keavney, B ; Morris, AP ; Heagerty, A ; Williams, B ; Harrap, SB ; Trynka, G ; Samani, NJ ; Guzik, TJ ; Charchar, FJ ; Tomaszewski, M (OXFORD UNIV PRESS, 2020-12-21)
    AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
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    The Association Between Selected Molecular Biomarkers and Ambulatory Blood Pressure Patterns in African Chronic Kidney Disease and Hypertensive Patients Compared With Normotensive Controls: Protocol for a Longitudinal Study
    Adeoye, AM ; Adebayo, O ; Abiola, B ; Iwalokun, B ; Tayo, B ; Charchar, F ; Ojo, A ; Cooper, R (JMIR PUBLICATIONS, INC, 2020-01-01)
    BACKGROUND: Chronic kidney disease (CKD) is a burgeoning epidemic in sub-Saharan Africa. Abnormal blood pressure variations are prevalent in CKD and potentiate the risk of cardiovascular morbidity and mortality. Certain genetic variants (angiotensin II receptor type 1 1166 A>C and angiotensin-converting enzyme insertion and deletion polymorphisms) and biomarkers such as interleukin-6, tumor necrosis factor, soluble (s) E-selectin, homocysteine, and highly sensitive C-reactive protein have been shown to affect blood pressure variability among non-African CKD, hypertensive. and nonhypertensive CKD population. However, the contributions of the pattern, genetic, and environmental determinants of ambulatory blood pressure in African CKD have not been characterized. Understanding these interactions may help to develop interventions to prevent major cardiovascular events among people with CKD. OBJECTIVE: The overarching objective of this study is to identify, document, and develop approaches to address related phenomic, genetic, and environmental determinants of ambulatory blood pressure patterns in African CKD and non-CKD hypertensive patients compared with normotensive controls. METHODS: This is a longitudinal short-term follow-up study of 200 adult subjects with CKD and 200 each of age-matched hypertensives without CKD and apparently healthy controls. Demographic information, detailed clinical profile, electrocardiography, echocardiography, and 24-hr ambulatory blood pressure measurements will be obtained. Blood samples will be collected to determine albumin-creatinine ratio, fasting plasma glucose, lipid profile, electrolytes, urea and creatinine, C-reactive protein, serum homocysteine, fibroblast growth factor-23, and complete blood count, while 2 mL blood aliquot will be collected in EDTA (ethylenediaminetetraacetic acid) tubes and mixed using an electronic rolling system to prevent blood clots and subsequently used for DNA extraction and genetic analysis. RESULTS: A total of 239 participants have been recruited so far, and it is expected that the recruitment phase will be complete in June 2020. The follow-up phase will continue with data analysis and publications of results. CONCLUSIONS: This study will help stratify Nigerian CKD patients phenotypically and genotypically in terms of their blood pressure variations with implications for targeted interventions and timing of medications to improve prognosis. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14820.
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    Molecular insights into genome-wide association studies of chronic kidney disease-defining traits
    Xu, X ; Eales, JM ; Akbarov, A ; Guo, H ; Becker, L ; Talavera, D ; Ashraf, F ; Nawaz, J ; Pramanik, S ; Bowes, J ; Jiang, X ; Dormer, J ; Denniff, M ; Antczak, A ; Szulinska, M ; Wise, I ; Prestes, PR ; Glyda, M ; Bogdanski, P ; Zukowska-Szczechowska, E ; Berzuini, C ; Woolf, AS ; Samani, NJ ; Charchar, FJ ; Tomaszewski, M (NATURE PUBLISHING GROUP, 2018-11-22)
    Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
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    May Measurement Month 2017: Results of 39 national blood pressure screening programmes
    Poulter, NR ; Borghi, C ; Castillo, RR ; Charchar, FJ ; Ramirez, AJ ; Schlaich, MP ; Schutte, AE ; Stergiou, G ; Unger, T ; Wainford, RD ; Beaney, T (OXFORD UNIV PRESS, 2019-04-01)
    Raised blood pressure is the biggest single risk factor responsible for mortality worldwide. Despite this, the majority of people with hypertension are unaware of having it, are untreated, or are on treatment but uncontrolled. May Measurement Month is a global campaign initiated by the International Society of Hypertension with the aim of raising awareness of high blood pressure. In the first year of the campaign in 2017, over 1.2 million people were screened in 80 countries across the world, finding over 100 000 people with hypertension who were not on treatment and over 150 000 people on anti-hypertensive treatment who were not controlled. The individual national results from 39 countries are presented in this supplement. In this article, we discuss the background to the campaign, along with some of the logistical and methodological challenges that were faced in setting up the campaign, and in collecting and analysing the data from such a large cross-sectional study. With the lessons learned from the 2017 campaign, the campaign was repeated in 2018 and is to be repeated again in 2019.
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    SLC2A9 Is a High-Capacity Urate Transporter in Humans
    Caulfield, MJ ; Munroe, PB ; O'Neill, D ; Witkowska, K ; Charchar, FJ ; Doblado, M ; Evans, S ; Eyheramendy, S ; Onipinla, A ; Howard, P ; Shaw-Hawkins, S ; Dobson, RJ ; Wallace, C ; Newhouse, SJ ; Brown, M ; Connell, JM ; Dominiczak, A ; Farrall, M ; Lathrop, GM ; Samani, NJ ; Kumari, M ; Marmot, M ; Brunner, E ; Chambers, J ; Elliott, P ; Kooner, J ; Laan, M ; Org, E ; Veldre, G ; Viigimaa, M ; Cappuccio, FP ; Ji, C ; Iacone, R ; Strazzullo, P ; Moley, KH ; Cheeseman, C ; Hattersley, A (PUBLIC LIBRARY SCIENCE, 2008-10-01)
    BACKGROUND: Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. METHODS AND FINDINGS: We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82). CONCLUSIONS: This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.
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    Epigenetic Modifications in Essential Hypertension
    Wise, IA ; Charchar, FJ (MDPI, 2016-04-01)
    Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world's leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual's risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development.
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    Urotensin-II System in Genetic Control of Blood Pressure and Renal Function
    Debiec, R ; Christofidou, P ; Denniff, M ; Bloomer, LD ; Bogdanski, P ; Wojnar, L ; Musialik, K ; Charchar, FJ ; Thompson, JR ; Waterworth, D ; Song, K ; Vollenweider, P ; Waeber, G ; Zukowska-Szczechowska, E ; Samani, NJ ; Lambert, D ; Tomaszewski, M ; Armando, I (PUBLIC LIBRARY SCIENCE, 2013-12-31)
    Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.