scholarly journals Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

2018 ◽  
Vol 51 (3) ◽  
pp. 1287-1300 ◽  
Author(s):  
Manel Vera ◽  
Sergi Torramade-Moix ◽  
Susana Martin-Rodriguez ◽  
Aleix Cases ◽  
Josep M. Cruzado ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Glutathione Peroxidase ◽  
Antioxidant Properties ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Oxygen Species ◽  
Radical Oxygen Species ◽  
Anti Inflammatory

Background/Aims: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. Methods: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. Results: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. Conclusion: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population.

Abstract 357: Antioxidant and Anti-inflammatory Strategies Prevent Endothelial Dysfunction in Chronic Kidney Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Marta Palomo ◽  
Susana Martin-Rodriguez ◽  
Manel Vera ◽  
Josep Maria Cruzado ◽  
Jose Rivera ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Antioxidant Enzyme ◽  
Inhibitory Effect ◽  
Ros Generation ◽  
Protective Effects ◽  
Anti Inflammatory ◽  
Enzyme Mimetics

Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by the development of endothelial dysfunction (ED), with development of a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. The effect of anti-inflammatory and antioxidant strategies on the endothelium has been evaluated in an in vitro model of ED in uremia. Endothelial cells (ECs) were pretreated with the antioxidant enzyme mimetics ebselen, EUK-134 and EUK-118; the flavonoids apigenin, genistein and quercetin, with both antioxidant and anti-inflammatory potential; and two commercially available compounds: N-acetylcysteine (NAC) and defibrotide (DF). There is increasing evidence demonstrating that both NAC and DF exhibit both properties. ECs were exposed to medium containing serum from patients on dialysis (n=10) or from healthy donors (n=15). Changes in the expression of the adhesion receptor ICAM-1 and the production of intracellular reactive oxygen species (ROS) were assessed. Activation of inflammation-related proteins p38 MAPK and NFkappaB (NFκB) were also evaluated. Exposure of ECs to uremic media resulted in a significantly increased expression of ICAM-1, overproduction of ROS and activation of p38MAPK and NFκB compared to control ECs (p<0.05). Ebselen, EUK 134, and EUK118 inhibited ICAM-1 expression and ROS generation in the uremic condition (p<0.01). Regarding flavonoids, only quercetin showed a moderated but significant inhibitory effect on both parameters (p<0.05). NAC and DF exhibited a protective effect on ECs exposed to the uremic insult (p<0.05 for ICAM-1 expression and ROS generation). All the compounds reduced p38MAPK activation (p<0.05). The antioxidant-enzyme mimetics and NAC were able to inhibit the activation of NFκB induced by the uremic media (p<0.05). Endothelial dysfunction associated with CKD is considered to be the first step in the progression of atherosclerosis. Our results indicate that the antioxidant enzyme mimetics, NAC and DF exhibit not only antioxidant but also anti-inflammatory effects on the endothelium. Therefore, further research on the protective effects of these compounds may provide new strategies for the prevention of the cardiovascular complications in uremia.

scholarly journals Inflammation and Oxidative Stress in Chronic Kidney Disease—Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites

2019 ◽  
Vol 21 (1) ◽  
pp. 263 ◽  
Author(s):  
Shara Francesca Rapa ◽  
Biagio Raffaele Di Iorio ◽  
Pietro Campiglia ◽  
August Heidland ◽  
Stefania Marzocco
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Antioxidant Properties ◽  
Small Sample ◽  
Beneficial Effects ◽  
Antioxidant Agents ◽  
Antioxidative Agents ◽  
Anti Inflammatory ◽  
And Oxidative Stress

Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.

scholarly journals Most exposed: the endothelium in chronic kidney disease

2019 ◽  
Vol 35 (9) ◽  
pp. 1478-1487 ◽  
Author(s):  
Marc Vila Cuenca ◽  
Peter L Hordijk ◽  
Marc G Vervloet
Keyword(s):  
Risk Factors ◽  
Reactive Oxygen Species ◽  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Oxygen Species ◽  
Pathological Changes ◽  
Endothelial Lining ◽  
Traditional Risk Factors

Abstract Accumulating evidence indicates that the pathological changes of the endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Non-traditional risk factors related to CKD are associated with the incidence of cardiovascular disease, but their role in uraemic endothelial dysfunction has often been disregarded. In this context, soluble α-Klotho and vitamin D are of importance to maintain endothelial integrity, but their concentrations decline in CKD, thereby contributing to the dysfunction of the endothelial lining. These hormonal disturbances are accompanied by an increment of circulating fibroblast growth factor-23 and phosphate, both exacerbating endothelial toxicities. Furthermore, impaired renal function leads to an increment of inflammatory mediators, reactive oxygen species and uraemic toxins that further aggravate the endothelial abnormalities and in turn also inhibit the regeneration of disrupted endothelial lining. Here, we highlight the distinct endothelial alterations mediated by the abovementioned non-traditional risk factors as demonstrated in experimental studies and connect these to pathological changes in CKD patients, which are driven by endothelial disturbances, other than atherosclerosis. In addition, we describe therapeutic strategies that may promote restoration of endothelial abnormalities by modulating imbalanced mineral homoeostasis and attenuate the impact of uraemic retention molecules, inflammatory mediators and reactive oxygen species. A clinical perspective on endothelial dysfunction in CKD may translate into reduced structural and functional abnormalities of the vessel wall in CKD, and ultimately improved cardiovascular disease.

scholarly journals Association of Individual Non-Steroidal Anti-Inflammatory Drugs and Chronic Kidney Disease: A Population-Based Case Control Study

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0122899 ◽  
Author(s):  
Ylenia Ingrasciotta ◽  
Janet Sultana ◽  
Francesco Giorgianni ◽  
Andrea Fontana ◽  
Antonio Santangelo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Case Control Study ◽  
Population Based ◽  
Case Control ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Control Study

scholarly journals Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease

2018 ◽  
Vol 314 (3) ◽  
pp. F423-F429 ◽  
Author(s):  
Danielle L. Kirkman ◽  
Bryce J. Muth ◽  
Meghan G. Ramick ◽  
Raymond R. Townsend ◽  
David G. Edwards
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Local Heating ◽  
Reactive Oxygen ◽  
Microvascular Dysfunction ◽  
Healthy Controls ◽  
Oxygen Species ◽  
Cutaneous Vasodilation

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3–5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg−1·1.73 m−2] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg−1·1.73 m−2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.

Abstract 346: Mice Overexpressing Renin: a New Model of Progressive Chronic Kidney Disease

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Anne-Cecile Huby ◽  
Ahmed Abed ◽  
Panos Kavvadas ◽  
Carlo Alfieri ◽  
Maria-Pia Rastaldi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Cell Adhesion ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Renal Disease ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Filtration Barrier ◽  
Human Pathology ◽  
Cell Adhesion Molecule 1

Background: Hypertension-induced chronic kidney disease in mouse models is quite fast and consequently away from the human pathology. There is an increasing need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. Aim: Our objective was dual: to investigate whether mice overexpressing renin ectopically at constant and high levels by genetic clamping (RenTg) could mimic kinetics and the physiopathological characteristics of hypertension-induced CKD and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD. Results: We found that RenTg mice are hypertensive (123±7 vs to 90±2 mm Hg for the wt age-matched animals, p<0.05) and slightly albuminuric (22.1±5.3 vs. 5.2±0.4 g/mol, p<0.01) as early as 3 month old. At this age, the expressions of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are 4-5 fold increased in the renal cortical vasculature indicating the beginning of endothelial dysfunction. Five month-old RenTg mice show perivascular and periglomerular infiltrations of macrophages and their GFR is starting to decrease(-10%). At 8 months, the renal cortex of RenTg mice is altered by leukocyte invasion, decreased expression of nephrin (a protein controlling filtration barrier), increased expression of KIM-1 (a protein typical of tubular cell stress) and of several pro-fibrotic agents of the TGFbeta family, and establishment of fibrotic lesions. At the age of 12 months, RenTg mice display several lesions of renal structure typical of hypertensive renal disease (such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion, tubular dilation), important proteinuria (138±20 g/mol) and a 55% fall of GFR. Conclusions: The RenTg strain develops progressively with age CKD. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide a useful tool allowing to gain new insights into the mechanisms of chronic renal failure and to identify new targets for arresting and/or reversing the development of CKD

scholarly journals Calcific Uremic Arteriolopathy: Pathophysiology, Reactive Oxygen Species and Therapeutic Approaches

2010 ◽  
Vol 3 (2) ◽  
pp. 109-121 ◽  
Author(s):  
Kurt M. Sowers ◽  
Melvin R. Hayden
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Chronic Kidney Disease ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Vascular Smooth Muscle ◽  
Reactive Oxygen ◽  
Morbidity And Mortality ◽  
Oxygen Species ◽  
Calcific Uremic Arteriolopathy

Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and reported on a global scale. The uremic milieu predisposes to multiple metabolic toxicities including increased levels of reactive oxygen species and inflammation. Increased oxidative stress and inflammation promote this arteriolopathy by adversely affecting endothelial function resulting in a prothrombotic milieu and significant remodeling effects on vascular smooth muscle cells. These arteriolar pathological effects include intimal hyperplasia, inflammation, endovascular fibrosis and vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Systemic factors promoting this vascular condition include elevated calcium, parathyroid hormone and hyperphosphatemia with consequent increases in the calcium × phosphate product. The uremic milieu contributes to a marked increased in upstream reactive oxygen species—oxidative stress and subsequent downstream increased inflammation, in part, via activation of the nuclear transcription factor NFκB and associated downstream cytokine pathways. Consitutive anti-calcification proteins such as Fetuin-A and matrix GLA proteins and their signaling pathways may be decreased, which further contributes to medial vascular calcification. The resulting clinical entity is painful, debilitating and contributes to the excess morbidity and mortality associated with chronic kidney disease and end stage renal disease. These same histopathologic conditions also occur in patients without uremia and therefore, the term calcific obliterative arteriolopathy could be utilized in these conditions.

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