Coupling between the TRPC3 ion channel and the NCX1 transporter contributed to VEGF-induced ERK1/2 activation and angiogenesis in human primary endothelial cells

This work was directly funded by the Barts and the London National Institute of Health Research (NIHR) Cardiovascular Biomedical Research Unit. Support to PA and MMY by the Barts Health “Diabetic Kidney Disease Centre,” supported and funded by the Barts and the London Charity (Grant Number 577-2348) is gratefully acknowledged. SAE receives funding from The Institute of Cancer Research and Cancer Research United Kingdom Grant C309/A8274. The authors wish to thank Sam Ranasinghe (University College London) for assistance with the FLIPR – Tetra assays

Myocardial bioenergetic abnormalities in experimental uremia.

PURPOSE: Cardiac bioenergetics are known to be abnormal in experimental uremia as exemplified by a reduced phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. However, the progression of these bioenergetic changes during the development of uremia still requires further study and was therefore investigated at baseline, 4 weeks and 8 weeks after partial nephrectomy (PNx). METHODS: A two-stage PNx uremia model in male Wistar rats was used to explore in vivo cardiac and skeletal muscles' bioenergetic changes over time. High-energy phosphate nucleotides were determined by phosphorus-31 nuclear magnetic resonance ((31)P-NMR) and capillary zone electrophoresis. RESULTS: (31)P-NMR spectroscopy revealed lower PCr/ATP ratios in PNx hearts compared to sham (SH)-operated animals 4 weeks after PNx (median values given ± SD, 0.64±0.16 PNx, 1.13±0.31 SH, P<0.02). However, 8 weeks after PNx, the same ratio was more comparable between the two groups (0.84±0.15 PNx, 1.04±0.44 SH, P= not significant), suggestive of an adaptive mechanism. When 8-week hearts were prestressed with dobutamine, the PCr/ATP ratio was again lower in the PNx group (1.08±0.36 PNx, 1.55±0.38 SH, P<0.02), indicating a reduced energy reserve during the progression of uremic heart disease. (31)P-NMR data were confirmed by capillary zone electrophoresis, and the changes in myocardial bioenergetics were replicated in the skeletal muscle. CONCLUSION: This study provides evidence of the changes that occur in myocardial energetics in experimental uremia and highlights how skeletal muscle bioenergetics mirror those found in the cardiac tissue and so might potentially serve as a practical surrogate tissue during clinical cardiac NMR investigations

A cohort study on the rate of progression of diabetic chronic kidney disease in different ethnic groups.

OBJECTIVE: To compare the rate of progression of diabetic chronic kidney disease in different ethnic groups. DESIGN: Prospective longitudinal observational study. PARTICIPANTS: All new patients attending a tertiary renal unit in east London with diabetic chronic kidney disease between 2000 and 2007 and followed up till 2009 were included. Patients presenting with acute end-stage kidney failure were excluded. MAIN OUTCOME MEASURES: The primary outcome was annual decline in the estimated glomerular filtration rate (eGFR) in different ethnic groups. Secondary end points were the number of patients developing end-stage kidney failure and total mortality during the study period. RESULTS: 329 patients (age 60±11.9 years, 208 men) were studied comprising 149 south Asian, 105 White and 75 Black patients. Mean follow-up was 6.0±2.3, 5.0±2.7 and 5.6±2.4 years for White, Black and south Asian patients, respectively. South Asian patients were younger and had a higher baseline eGFR, but both systolic and diastolic blood pressures were higher in Black patients (p<0.05). Baseline proteinuria was highest for the south Asian group followed by the White and Black groups. Adjusted linear regression analysis showed that an annual decline in eGFR was not significantly different between the three groups. The numbers of patients developing end-stage kidney failure and total mortality were also not significantly different between the three groups. ACE or angiotensin receptor blockers use, and glycated haemoglobin were similar at baseline and throughout the study period. CONCLUSIONS: We conclude that ethnicity is not an independent factor in the rate of progression renal failure in patients with diabetic chronic kidney disease

The role of salt intake and salt sensitivity in the management of hypertension in South Asian people with chronic kidney disease: A randomized controlled trial

Background The effectiveness of salt restriction to lower blood pressure (BP) in Bangladeshi patients with chronic kidney disease (CKD) is uncertain. Objective To test the hypothesis that a tailored intervention intended to reduce salt intake in addition to standard care will achieve a greater reduction in BP in UK Bangladeshi patients with CKD than standard care alone. Design A randomised parallel-group controlled trial conducted over a 6 month period. Setting A tertiary renal unit based in acute care hospital in East London. Participants 56 adult participants of Bangladeshi origin with CKD and BP >130/80 mm Hg or on antihypertensive medication. Intervention Participants were randomly allocated to receive a tailored low-salt diet or the standard low-salt advice. BP medication, physical activity and weight were monitored. Main outcome measures The primary outcome was change in ambulatory BP. Adherence to dietary advice was assessed by measurement of 24 h urinary salt excretion. Results Of 56 participants randomised, six withdrew at the start of the study. During the study, one intervention group participant died, one control group participant moved to Bangladesh. Data were available for the primary endpoint on 48 participants. Compared with control group the intervention urinary sodium excretion fell from 260 mmol/d to 103 mmol/d (131 to 76, p<0.001) at 6 months and resulted in mean (95% CI) falls in 24 h systolic/diastolic BP of 8 mm Hg (11 to 5)/2 (?4 to 2) both p<0.001. Conclusions A tailored intervention can achieve moderate salt restriction in patients with CKD, resulting in clinically meaningful falls in BP independent of hypertensive medication

Membranous nephropathy: a retrospective observational study of membranous nephropathy in north east and central London

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Work on this study was supported in part by grants from the European Union, FP7 (EURenOmics grant agreement 2012-305608)

Inhibition of Bruton's TK regulates macrophage NF-kappa B and NLRP3 inflammasome activation in metabolic inflammation

Background and Purpose: There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF-\u3baB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity. Experimental Approach: Using an in vivo model of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti-inflammatory medication to treat metabolic inflammation. Key Results: HFD-feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice decreased the activation of NF-\u3baB and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS-1/Akt/GSK-3\u3b2 pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF-\u3baB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular target of ibrutinib. Conclusion and Implications: We provide \u201cproof of concept\u201d evidence that BTK is a novel therapeutic target for the treatment of diet-induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti-inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease

Semi-automated non-target processing in GC × GC–MS metabolomics analysis: applicability for biomedical studies

Due to the complexity of typical metabolomics samples and the many steps required to obtain quantitative data in GC × GC–MS consisting of deconvolution, peak picking, peak merging, and integration, the unbiased non-target quantification of GC × GC–MS data still poses a major challenge in metabolomics analysis. The feasibility of using commercially available software for non-target processing of GC × GC–MS data was assessed. For this purpose a set of mouse liver samples (24 study samples and five quality control (QC) samples prepared from the study samples) were measured with GC × GC–MS and GC–MS to study the development and progression of insulin resistance, a primary characteristic of diabetes type 2. A total of 170 and 691 peaks were quantified in, respectively, the GC–MS and GC × GC–MS data for all study and QC samples. The quantitative results for the QC samples were compared to assess the quality of semi-automated GC × GC–MS processing compared to targeted GC–MS processing which involved time-consuming manual correction of all wrongly integrated metabolites and was considered as golden standard. The relative standard deviations (RSDs) obtained with GC × GC–MS were somewhat higher than with GC–MS, due to less accurate processing. Still, the biological information in the study samples was preserved and the added value of GC × GC–MS was demonstrated; many additional candidate biomarkers were found with GC × GC–MS compared to GC–MS