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The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic l-arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate–nitrite–NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.Nitric oxide (NO) has important roles in the regulation of kidney, cardiovascular and metabolic functions. This Review discusses the physiological roles of NO and its effects on kidney function, as well as its association with cardiometabolic complications and novel approaches to restoring NO homeostasis.

Decreased circulating levels of hydrogen sulfide (H2S) are associated with higher mortality following myocardial ischemia. This study aimed at determining the long-term dose-dependent effects of sodium hydrosulfide (NaSH) administration on myocardial ischemia-reperfusion (IR) injury. Male rats were divided into control and NaSH groups that were treated for 9 weeks with daily intraperitoneal injections of normal saline or NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg), respectively. At the end of the study, hearts from all rats were isolated and hemodynamic parameters were recorded during baseline and following IR. In isolated hearts, infarct size, oxidative stress indices as well as mRNA expression of H2S-, nitric oxide (NO)-producing enzymes, and inflammatory markers were measured. In heart tissue following IR, low doses of NaSH (0.28 and 0.56 mg/kg) had no effect, whereas an intermediate dose (1.6 mg/kg), improved recovery of hemodynamic parameters, decreased infarct size, and decreased oxidative stress. It also increased expression of cystathionine γ-lyase (CSE), Raf kinase inhibitor protein (RKIP), endothelial NO synthase (eNOS), and neuronal NOS (nNOS), as well as decreased expression of inducible NOS (iNOS) and nuclear factor kappa-B (NF-κB). At the high dose of 5.6 mg/kg, NaSH administration was associated with worse recovery of hemodynamic parameters and increased infarct size as well as increased oxidative stress. This dose also decreased expression of CSE, RKIP, and eNOS and increased expression of iNOS and NF-κB. In conclusion, chronic treatment with NaSH has a U-shaped concentration effect on IR injury in heart tissue. An intermediate dose was associated with higher CSE-derived H2S, lower iNOS-derived NO, lower oxidative stress, and inflammation in heart tissue following IR.

Background/objectivesMaternal obesity together with androgen excess in mice negatively affects placental function and maternal and fetal liver function as demonstrated by increased triglyceride content with dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage. To identify changes in molecular pathways that might promote diseases in adulthood, we performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess.MethodsAfter ten weeks on a control diet (CD) or high fat/high sugar-diet, dams were mated with males fed the CD. Between gestational day (GD) 16.5 and GD 18.5, mice were injected with vehicle or dihydrotestosterone (DHT) and sacrificed at GD 18.5 prior to dissection of the placentas and fetal livers. Four pools of female placentas and fetal livers were subjected to a global proteomic analysis. Total and phosphorylated proteins were filtered by ANOVA q < 0.05, and this was followed by two-way ANOVA to determine the effect of maternal obesity and/or androgen exposure.ResultsIn placenta, phosphorylated ATP-citrate synthase was decreased due to maternal obesity, and phosphorylated catechol-O-methyltransferase (COMT) was differentially expressed due to the interaction between maternal diet and DHT exposure. In fetal liver, five total proteins and 48 proteins phosphorylated in one or more sites, were differentially expressed due to maternal obesity or androgen excess. In fetal liver, phosphorylated COMT expression was higher in fetus exposed to maternal obesity.ConclusionThese results suggest a common regulatory mechanism of catecholamine metabolism in the placenta and the fetal liver as demonstrated by higher phosphorylated COMT expression in the placenta and fetal liver from animals exposed to diet-induced maternal obesity and lower expression of phosphorylated COMT in animals exposed to maternal androgen excess.

Background: Acute kidney injury (AKI) is a sudden episode of kidney failure which is frequently observed at intensive care units and related to high morbidity/mortality. Although AKI can have many different causes, ischemia–reperfusion (IR) injury is the main cause of AKI. Mechanistically, NADPH oxidases (NOXs) are involved in the pathophysiology contributing to oxidative stress following IR. Previous reports have indicated that knockout of NOX4 may offer protection in cardiac and brain IR, but there is currently less knowledge about how this could be exploited therapeutically and whether this could have significant protection in IR-induced AKI. Aim: To investigate the hypothesis that a novel and specific NOX4 inhibitor (GLX7013114) may have therapeutic potential on kidney and mitochondrial function in a mouse model of IR-induced AKI. Methods: Kidneys of male C57BL/6J mice were clamped for 20 min, and the NOX4 inhibitor (GLX7013114) was administered via osmotic minipump during reperfusion. Following 3 days of reperfusion, kidney function (i.e., glomerular filtration rate, GFR) was calculated from FITC-inulin clearance and mitochondrial function was assessed by high-resolution respirometry. Renal histopathological evaluations (i.e., hematoxylin–eosin) and TUNEL staining were performed for apoptotic evaluation. Results: NOX4 inhibition during reperfusion significantly improved kidney function, as evidenced by a better-maintained GFR (p < 0.05) and lower levels of blood urea nitrogen (p < 0.05) compared to untreated IR animals. Moreover, IR caused significant tubular injuries that were attenuated by simultaneous NOX4 inhibition (p < 0.01). In addition, the level of renal apoptosis was significantly reduced in IR animals with NOX4 inhibition (p < 0.05). These favorable effects of the NOX4 inhibitor were accompanied by enhanced Nrf2 Ser40 phosphorylation and conserved mitochondrial function, as evidenced by the better-preserved activity of all mitochondrial complexes. Conclusion: Specific NOX4 inhibition, at the time of reperfusion, significantly preserves mitochondrial and kidney function. These novel findings may have clinical implications for future treatments aimed at preventing AKI and related adverse events, especially in high-risk hospitalized patients.

Correspondence to Dr Susanna C Larsson, Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden; susanna.larsson@ki.se Observational studies have found that coffee consumption is inversely associated with risk of incident gout but inconsistently with serum uric acid concentrations.1–3 The causality of the associations is, however, uncertain since observational studies are susceptible to confounding and reverse causation bias. Genetic variants with an explicit impact on a modifiable exposure, such as a biomarker or habitual behaviour like coffee consumption, can be used as instrumental variables (proxies) for the exposure to improve causal inference.4 This method, known as Mendelian randomisation, builds on Mendel’s second law and the fact that genetic variants are randomly assorted during meiosis. [...]results from Mendelian randomisation studies are less prone to bias due to confounding and reverse causality. A genome-wide association study from the Coffee and Caffeine Genetics Consortium identified 10 single-nucleotide polymorphisms (SNPs), at eight loci, associated with coffee consumption (online supplementary table S1).5 We excluded three SNPs that did not exceed the genome-wide significance threshold (p <5×10−8) and two SNPs in linkage disequilibrium (r 2 >0.6) (online supplementary table S1), leaving five independent SNPs for the main analyses.

Cannabinoid receptor 1 (CB R) is widely distributed in the central nervous system, in excitatory and inhibitory neurons, and in astrocytes. CB R agonists impair cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. Based on the knowledge that eCBs are released upon high frequency neuronal firing, we hypothesized that the influence of eCBs upon LTP could change according to the paradigm of LTP induction. We thus tested the influence of eCBs on hippocampal LTP using two θ-burst protocols that induce either a weak or a strong LTP. LTP induced by a weak-θ-burst protocol is facilitated while preventing the endogenous activation of CB Rs. In contrast, the same procedures lead to inhibition of LTP induced by the strong-θ-burst protocol, suggestive of a facilitatory action of eCBs upon strong LTP. Accordingly, an inhibitor of the metabolism of the predominant eCB in the hippocampus, 2-arachidonoyl-glycerol (2-AG), facilitates strong LTP. The facilitatory action of endogenous CB R activation does not require the activity of inhibitory A1 adenosine receptors, is not affected by inhibition of astrocytic metabolism, but involves inhibitory GABAergic transmission. The continuous activation of CB Rs via exogenous cannabinoids, or by drugs known to prevent metabolism of the non-prevalent hippocampal eCB, anandamide, inhibited LTP. We conclude that endogenous activation of CB Rs by physiologically formed eCBs exerts a fine-tune homeostatic control of LTP in the hippocampus, acting as a high-pass filter, therefore likely reducing the signal-to-noise ratio of synaptic strengthening.

Background and Aim: The association of habitual intakes of dietary nitrate (NO3−) and nitrite (NO2−) with blood pressure and renal function is not clear. Here, we investigated a potential effect of dietary NO3− and NO2− on the occurrence of hypertension (HTN) and chronic kidney disease (CKD). Methods: A total of 2799 Iranian adults aged ≥20 years, participating in the Tehran Lipid and Glucose Study (TLGS), were included and followed for a median of 5.8 years. Dietary intakes of NO3− and NO2− were estimated using a semi-quantitative food frequency questionnaire. Demographics, anthropometrics, blood pressure and biochemical variables were evaluated at baseline and during follow-up examinations. To identify the odds ratio (OR) and 95% confidence interval (CI) of HTN and CKD across tertile categories of residual energy-adjusted NO3− and NO2− intakes, multivariate logistic regression models were used. Results: Dietary intake of NO3− had no significant association with the risk of HTN or CKD. Compared to the lowest tertile category (median intake < 6.04 mg/day), the highest intake (median intake ≥ 12.7 mg/day) of dietary NO2− was accompanied with a significant reduced risk of HTN, in the fully adjusted model (OR = 0.58, 95% CI = 0.33–0.98; p for trend = 0.054). The highest compared to the lowest tertile of dietary NO2− was also accompanied with a reduced risk of CKD (OR = 0.50, 95% CI = 0.24–0.89, p for trend = 0.07). Conclusion: Our findings indicated that higher intakes of NO2− might be an independent dietary protective factor against the development of HTN and CKD, which are major risk factors for adverse cardiovascular events.

Background Considering the lack of data on the association between habitual dietary intakes of nitrate (NO 3 − ) and nitrite (NO 2 − ) and cardiovascular events, we assessed possible effects of dietary NO 3 − and NO 2 − , in the context of total antioxidant capacity (TAC) of the diet, with the risk of cardiovascular (CVD) outcomes. Methods Adult men and women without CVD ( n  = 2369) were recruited from the Tehran Lipid and Glucose Study and were followed for a mean of 6.7 years. Dietary NO 3 − and NO 2 − intakes, as well as dietary TAC and nitric oxide (NO) index were assessed at baseline (2006–2008). Multivariable-adjusted Cox proportional hazards regression models were used to estimate risk of CVD above and below median of dietary intakes of NO 3 − /NO 2 − and dietary TAC and NO index. Due to a significant interaction between NO 3 − /NO 2 − intake and TAC, stratified analyses were done for < and ≥ median dietary TAC. Results Daily mean (SD) dietary NO 3 − and NO 2 − intakes were 460 (195) and 9.5 (3.9) mg; mean (SD) dietary TAC and NO index was 1406 (740) and 338 (197) μmol trolox equivalent (TE)/100 g. In subjects with lower dietary TAC, higher intake of NO 3 − (≥ 430 mg/d) was accompanied with an increased risk of CVD (HR = 3.28, 95% CI = 1.54–6.99). There were no significant associations between dietary intakes of NO 2 − , TAC of the diet and NO index with the occurrence of CVD events during the study follow-up. Conclusion High habitual intake of NO 3 − , in the context of low TAC of the food, may be associated with the risk of CVD outcomes.