Rhian Touyz

Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

Rats and mice are commonly used as experimental models in hypertension research. Critical to the field is information on blood pressure in these models at baseline, over time, and following interventions. While there have been advancements in the approaches to measure blood pressure in mice and rats, the 2 methods that are commonly used include invasive radiotelemetry and the noninvasive tail-cuff technique. Both methods have advantages and disadvantages as highlighted in the 2005 American Heart Association statement paper on recommendations for blood pressure measurement in experimental animals. 1 Because assessment by implantable radiotelemetry allows for continuous and direct measurement of blood pressure, this has been considered as the standard. However, with this notion is the perception by some authors and reviewers that tail-cuff measurements are not acceptable in the reporting …

The following sections are included: Magnesium Balance Intestinal Absorption Kidney Absorption Hypomagnesaemia Hypermagnesaemia References

Background: Angiopoietin-like 2 (ANGPTL2) is a pro-inflammatory and pro-oxidant circulating protein that predicts and promotes chronic inflammatory diseases such as atherosclerosis in humans. Transgenic murine models demonstrated the deleterious role of ANGPTL2 in vascular diseases, while deletion of ANGPTL2 was protective. The nature of its role in cardiac tissues is, however, less clear. Indeed, in adult mice knocked down (KD) for ANGPTL2, we recently reported a mild left ventricular (LV) dysfunction originating from a congenital aortic valve stenosis, demonstrating that ANGPTL2 is essential to cardiac development and function.Hypothesis: Because we originally demonstrated that the KD of ANGPTL2 protected vascular endothelial function via an upregulation of arterial NOX4, promoting the beneficial production of dilatory H2O2, we tested the hypothesis that increased cardiac NOX4 could negatively affect cardiac redox and remodeling and contribute to LV dysfunction observed in adult Angptl2-KD mice.Methods and results: Cardiac expression and activity of NOX4 were higher in KD mice, promoting higher levels of cardiac H2O2 when compared to wild-type (WT) mice. Immunofluorescence showed that ANGPTL2 and NOX4 were co-expressed in cardiac cells from WT mice and both proteins co-immunoprecipitated in HEK293 cells, suggesting that ANGPTL2 and NOX4 physically interact. Pressure overload induced by transverse aortic constriction surgery (TAC) promoted LV systolic dysfunction in WT mice but did not further exacerbate the dysfunction in KD mice. Importantly, the severity of LV systolic dysfunction in KD mice (TAC …

Introduction We aimed to understand the impact of being a healthcare worker on the progression and outcomes of illness in individuals hospitalised because of post-COVID-19 complications.Materials and Methods The CISCO-19 study included patients hospitalised with COVID-19 and assessed baseline characteristics at index and multi-system phenotyping 28–60 days following discharge from hospital. Our analysis sought to compare the health and recovery metrics of healthcare workers within this cohort against those of non-healthcare professionals, considering variables like age, gender, cardiovascular risk, and severity of inflammation.Results A total of 168 patients, 28–60 days post their last hospital care, were assessed. Among them, 36 identified as healthcare workers. Comparatively, healthcare workers were found to be predominantly of a similar age to non-healthcare workers but had a higher proportion …

BackgroundThe associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain.MethodsA prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28–60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression …

Background Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear. Aims We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias. Methods Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17β-estradiol, dihydrotestosterone (DHT), and testosterone. Results In controls, testosterone and 17β-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < …

PurposeDisorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause.MethodsDetailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings.ResultsBy trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a …

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies …

Different cell channels and transporters tightly regulate cytoplasmic levels and the intraorganelle distribution of cations. Perturbations in these processes lead to human diseases that are frequently associated with kidney impairment. The family of melastatin-related transient receptor potential (TRPM) channels, which has eight members in mammals (TRPM1–TRPM8), includes ion channels that are highly permeable to divalent cations, such as Ca2+, Mg2+ and Zn2+ (TRPM1, TRPM3, TRPM6 and TRPM7), non-selective cation channels (TRPM2 and TRPM8) and monovalent cation-selective channels (TRPM4 and TRPM5). Three family members contain an enzymatic protein moiety: TRPM6 and TRPM7 are fused to α-kinase domains, whereas TRPM2 is linked to an ADP-ribose-binding NUDT9 homology domain. TRPM channels also function as crucial cellular sensors involved in many physiological processes …

Background Hypertension and vascular toxicity are major unwanted side effects of antiangiogenic drugs, such as vascular endothelial growth factor inhibitors (VEGFis), which are effective anticancer drugs but have unwanted side effects, including vascular toxicity and hypertension. Poly (ADP‐ribose) polymerase (PARP) inhibitors, used to treat ovarian and other cancers, have also been associated with elevated blood pressure. However, when patients with cancer receive both olaparib, a PARP inhibitor, and VEGFi, the risk of blood pressure elevation is reduced. Underlying molecular mechanisms are unclear, but PARP‐regulated transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a redox‐sensitive calcium channel, may be important. We investigated whether PARP/TRPM2 plays a role in VEGFi‐induced vascular dysfunction and whether PARP inhibition ameliorates the vasculopathy …

BackgroundMost studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.MethodsIn this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.FindingsStrong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal …

Background:The multisystem associations between baseline mental health status and coronavirus disease-19 (COVID)-19 illness trajectory are uncertain.Objectives:This article will investigate the associations between baseline mental health status and disease trajectory following COVID-19 hospitalization, which may have implications for practice and future research.Methods:The Chief Scientist Office Cardiovascular and Pulmonary Imaging in severe acute respiratory syndrome (SARS) COVID-19 study is a prospective, observational, multicenter, longitudinal, secondary care cohort study that assessed the time-course of multi-organ injury in posthospital survivors of COVID-19. Patients were assessed in-hospital, at 28–60 days after discharge and in the longer term using electronic health record linkage.Results:One hundred and fifty-two patients (mean±standard deviation [SD] age 54.3±11.8 years, 43% female, 40 …

Funding This work was supported by the British Heart Foundation (grant numbers: PG/17/2532884; RE/13/5/30177; RE/18/6134217). The trial sponsor is the Golden Jubilee Research Foundation. The British Heart Foundation has supported DC through a research fellowship (FS/14/15/30661). AEA and LH are supported by intramural funding from the National Heart Lung and Blood Institute.Disclosures C.B. is employed by the University of Glasgow, which holds consultancy and research agreements with companies that have commercial interests in the diagnosis and treatment of angina. The companies include Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, HeartFlow, Neovasc, Novartis, Siemens Healthcare, and Valo Health. K.G.O. has received consultant and speaker fees from Abbott Vascular and Volcano Corporation which manufacture pressure wires. He is an employee of Biosensors …

BACKGROUNDCOVID-19 is primarily a respiratory disease associated with cardiovascular damaging effects, where it is predicted that patients may develop cardiovascular disease (CVD), including hypertension, where endotheliitis is a risk factors for these adverse outcomes. Considering the relationship between the viral spike protein and the host’s ACE2, it is unclear whether this interaction is merely a mechanism of infection or whether it also contributes to vascular injury induced by SARS-CoV-2.METHODS AND RESULTSHuman endothelial cells (EC), previously shown to be resistant to SARS-CoV-2 infection, were exposed to recombinant S1p [(rS1p) 0.66 μg/mL] for 24h. Label-free quantitation of full proteome of ECs with/without rS1p stimulation were performed. Gene expression was assessed by RT-PCR and cytokine release was assessed by ELISA. Protein expression was assessed by immunoblotting …

BackgroundSleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea.MethodsCircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two …

Hypertension is the leading risk factor for cardiovascular disease and premature death among women globally. However, there is a fundamental lack of knowledge regarding the sex-specific pathophysiology of the condition. In addition, risk factors for hypertension and cardiovascular disease unique to women or female sex are insufficiently acknowledged in clinical guidelines. This review summarizes the existing evidence on women and female-specific risk factors and clinical management of hypertension, to identify critical knowledge gaps relevant to research, clinical practice, and women’s heart health awareness. Female-specific risk factors relate not only to reproduction, such as the association of gynecological conditions, adverse pregnancy outcomes or menopause with hypertension, but also to the specific roles of women in society and science, such as gender differences in received medical care and the …

Background:NOX4 activation has been implicated to have vasoprotective and blood pressure (BP)-lowering effects. Molecular mechanisms underlying this are unclear, but NOX4-induced regulation of the redox-sensitive Ca 2+ channel TRPM2 and effects on endothelial nitric oxide synthase (eNOS)-nitric oxide signalling may be important.Method:Wild-type and LinA3, renin-expressing hypertensive mice, were crossed with NOX4 knockout mice. Vascular function was measured by myography. Generation of superoxide (O 2-) and hydrogen peroxide (H 2 O 2) were assessed by lucigenin and amplex red, respectively, and Ca 2+ influx by Cal-520 fluorescence in rat aortic endothelial cells (RAEC).Results:BP was increased in NOX4KO, LinA3 and LinA3/NOX4KO mice. This was associated with endothelial dysfunction and vascular remodelling, with exaggerated effects in NOX4KO groups. The TRPM2 activator, ADPR …

Objective:In endothelial cells, Nox4 is the most prevalent isoform and, in contrast to other Noxes, which generate superoxide O2, Nox4 produces mainly H2O2. Low H2O2 levels have been described to lower blood pressure, which suggests that a certain level of reactive oxygen species (ROS) can have protective effects on the cardiovascular system. We demonstrated that TRPM2 is a target of H2O2 in vascular cells. TRPM2 is a redox-sensitive Ca2+ channel and once activated leads to Ca2 influx. Endothelial dysfunction involves a reduction in eNOS activation by Ca2+ and is potentiated in the absence of Nox4. As TRPM2 channel is a H2O2 sensor and regulates Ca2+ entry, we questioned whether protective Nox4 effect in endothelial cells involves the H2O2-TRPM2-Ca2+ axis, with consequent regulation of NO signalling.Design and Methods:WT and TTRhRen hypertensive mice were crossed with Nox4 KO mice …

Assessment of hypertensive tubulopathy for more than fifty animal models of hypertension in experimental pathology employs criteria that do not correspond to lesional descriptors for tubular lesions in clinical pathology. We provide a critical appraisal of experimental hypertension with the same approach used to estimate hypertensive renal tubulopathy in humans. Four models with different pathogenesis of hypertension were analyzed—chronic angiotensin (Ang) II–infused and renin-overexpressing (TTRhRen) mice, spontaneously hypertensive (SHR), and Goldblatt two-kidney one-clip (2K1C) rats. Mouse models, SHR, and the nonclipped kidney in 2K1C rats had no regular signs of hypertensive tubulopathy. Histopathology in animals was mild and limited to variations in the volume density of tubular lumen and epithelium, interstitial space, and interstitial collagen. Affected kidneys in animals demonstrated lesion …