Stress In Chronic Renal Failure Research Articles

Lower p66Shc promoter methylation in subjects with chronic renal failure.

ObjectiveTo determine the correlation between DNA methylation of p66Shc promoter and some markers of inflammatory and oxidative stress in chronic renal failure (CRF) patients compared with healthy subjects.MethodsAn observational cross-sectional study was conducted in the nephrology department at Sidi Bouzid Regional Hospital (Tunisia). In total, 39 patients with CRF and 37 healthy subjects were included. Several biochemical parameters were measured. Furthermore, markers of the oxidative and inflammatory status (MDA, TAS, SOD, and CRP) were evaluated. The p66Shc methylation status was determined using the methylation-specific PCR.ResultsOur results showed that levels of blood glucose, urea, creatinine, uric acid, ChT, TG, albuminuria, CRP and MDA were significantly elevated in CRF patients compared to controls. Furthermore, p66Shc promoter region was highly demethylated in CRF patients compared to healthy controls (84% vs 4%). Our data showed a positive correlation between p66Shc hypomethylation and levels of MDA (r = 0.93; p<0, 05) and CRP (r = 0.89; P <0, 05), as well as a significant negative correlation between p66Shc hypomethylation, TAS (r = -0.76; P <0, 05) and SOD (r = -0.77; p<0, 05) levels. Similarly, there was a positive correlation between p66Shc hypomethylation and the disease stages. Importantly, multiple regression analysis showed that p66shc DNA hypomethylation remains strongly correlated with MDA, CRP and stages of CRF.ConclusionThis study indicates that the DNA hypomethylation of p66shc promoter was correlated with oxidative and inflammatory stress and the disease stages in CRF patients.

The mitochondrial-targeted peptide SBT-20 ameliorates inflammation and oxidative stress in chronic renal failure.

Chronic renal failure (CRF) is the final outcome of the development of chronic kidney disease with different causes. Although CRF is a common clinical disease, its pathogenesis remains to be improved. SBT-20 belongs to a class of cell-permeable peptides that target the inner mitochondrial membrane, reduce reactive oxygen species (ROS), normalize electron transport chain function, and ATP generation. Our experiment was to evaluate whether SBT-20 affected the oxidative stress and inflammatory process of CRF. The levels of ROS production, mitochondrial membrane potential, NF- κB-p65, TNF-α, Drp1, and mfn2 were measured before and after SBT-20 treatment. We observed that SBT-20 treatment inhibited H2O2-induced mitochondrial ROS production. SBT-20 could also restore the mitochondrial membrane potential and reduce the elevated levels of NF-κB-p65 and TNF-α in HK-2 cells. In vivo, the renal function of CRF mice recovered after treating with SBT-20, the levels of necrotic cells and inflammation decreased, and the morphology of mitochondria recovered. The results showed that SBT-20 had a protective effect on CRF by reducing oxidative stress, inflammation progression via down-regulating of NF-κB-p65, TNF-α, and Drp1 and upregulating of Mfn2. These data support SBT-20 could be used as a potential preparation for CRF.

Diosgenin, a steroidal saponin, prevents hypertension, cardiac remodeling and oxidative stress in adenine induced chronic renal failure rats

Prevention of hypertension, cardiac remodeling and oxidative stress in chronic renal failure (CRF) rats by diosgenin.

Effects of Jianpi Qinghua Recipe on angiotensin II/NADPH oxidase pathway in 5/6 nephrectomized rats

To study the effect of Jianpi Qinghua Recipe ( JPQHR) on angiotensin II/NADPH oxidase pathway in 5/6 nephrectomized rat renal failure model and the underlying mechanisms. The animals were divided into 4 groups: the sham-operated group, the renal failure group, the JPQHR-treated group and the losartan-treated group. After 60-days therapy, serum nitrogen and creatinine were measured. The expression of angiotensin II type 1 receptor (AT1) protein and the expression of p47phox mRNA in renal tissue was determined. SOD and MDA were also examined. Compared with the sham-operated group, the levels of SCr and serum BUN and the AT1 protein and p47phox mRNA expression in the renal failure group were significantly increased. The activities of SOD in renal tissue from the renal failure group was significantly down-regulated while MDA was up-regulated (P<0.05). Compared with the renal failure group, the levels of SCr and serum BUN and the AT1 protein and p47phox mRNA expression in both JPQHR-treated group and losartan-treated group were significantly decreased. The activities of SOD in renal tissue from JPQHR-treated group and losartan-treated group were significantly up-regulated whereas the content of MDA were down-regulated (P<0.05). Compared with the losartan-treated group, the activities of SOD in renal tissue from the JPQHR-treated group was obviously increased (P<0.05), the decrease in AT1 protein and p47phox mRNA was more evident but not statistically different (P>0.05). The level of SCr and serum BUN and the content of MDA were also not statistically different (P>0.05). Through decrease the expression of angiotensin II and NADPH oxidase, JPQHR can reduce the oxidative stress in chronic renal failure and delay the renal fibrosis progression.

Role of AT1 receptors over the oxidative stress in chronic renal failure (CRF)

CRF is a progressive condition marked by deteriorating kidney function over time. Elevated blood pressure, renin‐angiotensin system and the imbalance of antioxidant defenses are involved in the progression of renal diseases. The aim of this study was to evaluate the effects of chronic treatment with angiotensin AT1 receptor blockade (Candesartan) in the oxidative stress and evolution of CRF. Wistar rats were divided in 3 groups: control (C, n=6), CRF (n=6) and CRF + Cand (n=6). CRF was induced by the 5/6 nephrectomy model. Treatment with Cand, 25 mg/Kg VO (2 weeks, daily) started 6 weeks after surgery. Creatinine clearance (CrCl) and TBARS (indicative of oxidative stress) were evaluated. Animals of CRF presented a reduction in CrCl and Cand treatment improves this effect (C 2,1±0,2 x CRF 0,9 ±0,1 x CRF + Cand 1,5±0,2 ml/min). Plasmatic levels of TBARS are raised in CRF and Cand treatment normalized this values (C 2,0±0,2 x CRF 3,6 ±0,06 x CRF +Cand 1,0 ± 0,3 nmoles/ml). These results suggest that blockade of AT1 receptor reduces oxidative stress and improve renal function in CRF rats. The reduction of oxidative stress can be an important factor against progression of renal disease.Supported by: CNPq

Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Prevents Oxidative Stress in Uremic Rats

Chronic renal failure causes left ventricular hypertrophy, but the molecular mechanisms involved remain unknown. We, therefore, investigated whether the mineralocorticoid receptor is implicated in the cardiac hypertrophy observed in uremic rats and whether mineralocorticoid receptor blockade could be protective in chronic renal failure. Experimental groups were: control rats, uremic rats (NPX) with 5/6 nephrectomy (5 weeks), and NPX rats fed with spironolactone for 5 weeks. Systolic blood pressure was increased in both NPX rats and NPX rats fed with spironolactone for 5 weeks. Echocardiography revealed concentric left ventricular hypertrophy in uremia, which was attenuated by spironolactone. Enlarged cardiomyocyte size was observed in both left and right ventricles of NPX rats, an effect that was prevented by spironolactone. Mineralocorticoid receptor antagonism attenuated the increase of ventricular brain natriuretic peptide mRNA levels induced by nephrectomy. Left ventricular gene expressions of aldosterone synthase, mineralocorticoid receptor, and hydroxysteroid dehydrogenase type 2 were the same in the 3 groups, whereas gene expression of the glucocorticoid receptor was significantly diminished in chronic renal failure rats. No significant differences in cardiac aldosterone were observed between control rats and NPX rats, although NPX rats fed with spironolactone for 5 weeks showed increased plasma aldosterone levels. However, a significant increase in serum and glucocorticoid-inducible kinase-1 mRNA expression and protein was present in the NPX group; spironolactone treatment significantly reduced serum and glucocorticoid-inducible kinase-1 mRNA and protein in the left ventricle. Uremic rats exhibited a significant increase of superoxide production and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits expression (NOX-2, NOX-4, and p47(phox)) in the left ventricle, which was prevented by the mineralocorticoid receptor antagonist. Our findings provide evidence of the beneficial effects of spironolactone in cardiac hypertrophy and cardiac oxidative stress in chronic renal failure.

Trace elements and oxidative stress in chronic renal failure

Trace elements and oxidative stress in chronic renal failure

Vascular repair and regulation in kidney disease: Overview

Vascular repair and regulation in kidney disease: Overview

Carbonyl stress in chronic renal failure: the effect of haemodialysis

Oxidative stress has been defined as a loss of balance between free radical production and the antioxidant systems. There have been many reports of increased production of oxidants and decreased levels of antioxidants in chronic renal failure (CRF) patients. An increase in oxidative stress may contribute to the development of oxidative protein damage in CRF. Our aim was to reveal oxidative modifications of plasma proteins by measuring 2,4-dinitrophenylhydrazine reactive carbonyl derivates (PCO), protein thiol (P-SH) and reduced glutathione (GSH) in predialytic uraemic and haemodialysed (HD) patients before and after dialysis. We included 20 predialytic uraemic patients, 20 HD patients and 20 healthy volunteers in our study. PCO concentration in predialytic uraemic patients increased compared with the concentration of the control group and this increase was more profound in HD patients. P-SH concentrations were significantly decreased in haemodialytic patients compared with those of controls. GSH level was higher in HD patients (both before and after dialysis). Increased PCO and decreased P-SH concentrations in all patient groups in comparison to the control subjects indicate increased protein oxidation. Our data in ESRD patients propose plasma protein carbonyl derivates and thiol concentrations as novel specific markers for oxidative protein damage.

Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: Impact on cardiovascular disease

Despite significant progress in renal replacement therapy, the mortality from cardiovascular disease (CVD) in patients with chronic renal failure (CRF) is many times higher than in the general population. The traditional risk factors are frequently present in CRF patients. However, based upon conventional risk factor analysis, these factors do not fully explain the extraordinary increase in morbidity and mortality in CVD among patients with CRF. Accumulating evidence suggests that CRF is associated with impaired endothelial cell function. In recent years, the role of endothelial dysfunction (ED) and excessive oxidative stress (OS) in the development of CVD has been highlighted. ED is an early feature of vascular disease in different diseases such diabetes, hypertension, hypercholesterolemia, and coronary heart disease. The precise mechanism which induces ED is not clear. Several factors however, including OS-related accumulation of uremic toxins, hypertension and shear stress, dyslipidemia with cytotoxic lipoprotein species such as small, dense low-density lipoprotein (LDL) particles, competitive inhibition of endothelial nitric oxide (NO) by increased production by asymmetrical dimethylarginine (ADMA) are pathogenic. In addition, it is known that excessive OS causes ED. An overproduction of reactive oxygen species (ROS) may injure the endothelial cell membrane, inactivate NO, and cause oxidation of an essential cofactor of nitric oxide synthase (NOS). Recent studies have demonstrated that an impaired endothelium-dependent vasodilation and OS are closely related to each other in patients with CRF.

Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients

Oxidative stress has been implicated in the cardiovascular complications that affect chronic renal failure patients on hemodialysis, though the physiologically relevant pathways mediating oxidative damage are poorly understood. It is known, however, that hemodialysis activates neutrophils, a well-characterized source of hydrogen peroxide and myeloperoxidase. The phagocyte-derived myeloperoxidase-hydrogen peroxide-chloride system generates hypochlorous acid, which reacts with tyrosine residues of proteins to form 3-chlorotyrosine. To explore the role of activated phagocytes in oxidative stress in chronic renal failure, we used 3-chlorotyrosine as a specific marker of myeloperoxidase activity. Utilizing isotope dilution gas chromatography-mass spectrometry, we compared 3-chlorotyrosine levels in plasma proteins of five patients on chronic hemodialysis therapy with those of age- and sex-matched healthy controls. The oxidized amino acid was present in the plasma proteins of 4 of the hemodialysis patients (3.5 ± 0.8 μmol per mol tyrosine) but was undetectable in the healthy subjects. Therefore, one pathway for oxidative stress in hemodialysis patients appears to involve hypochlorous acid generated by the myeloperoxidase system of activated phagocytes. We also examined intradialytic 3-chlorotyrosine levels using membranes that activate white blood cells and the alternative pathway of complement. Hemodialysis increased plasma myeloperoxidase and the expression of CD11b/CD18 by circulating phagocytes, but failed to demonstrably increase 3-chlorotyrosine levels. 3-chlorotyrosine was detectable in 12 of 19 samples in total, with significant intrasubject variability. Our observations suggest that oxidants generated by myeloperoxidase contribute to the increased oxidative stress observed in renal-failure patients but do not damage plasma proteins during the hemodialysis procedure itself.

Relevance of oxidative and carbonyl stress to long-term uremic complications

Oxidative stress is a disturbance of balance between oxidants and antioxidant species. The existence of an increased oxidative stress in chronic renal failure is supported by evidence of increased lipid, carbohydrate, and protein oxidation products in plasma and cell membrane. Recent studies have implicated the oxidative stress in the nonenzymatic biochemistry leading to irreversible protein modifications. Reactive oxygen species may directly alter proteins with the eventual formation of oxidized amino acids. Alternatively, reactive carbonyl compounds formed by the oxidation of carbohydrates and lipids may indirectly lead to advanced glycation or lipoxidation of proteins. Chronic uremia is associated with increased modification of protein caused by reactive carbonyl compounds derived from both carbohydrates and lipids. Increased carbonyl modification of proteins subsequently results in the rise of plasma and tissue contents of advanced glycation end products and advanced lipoxidation end products, in which the deleterious biological effects have been revealed. This article focuses on the irreversible nonenzymatic modification of proteins, which might, at least in part, contribute to the development of complications associated with chronic renal failure and long-term dialysis, such as atherosclerosis and dialysis-related amyloidosis.

Clinical Study: Oxidative Stress in Chronic Renal Failure

This study focuses on the oxidative stress in patients with severe chronic renal failure who are not undergoing dialysis treatment. The erythocyte levels, creatinine clearing and plasma-and cell activities of the following enzymes were determined: glutathione peroxidase (Gpx), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione transferase (GT). The concentrations of non-enzyme molecules such as total glutathione in both oxidized and reduced forms, and malonyldialdehyde (MDA) were also measured.The obtained values were compared with those in healthy blood donors of comparable age and social status. The results indicate that chronic renal patients have lower glutathione levels and reduced activities of glutathione peroxidase and of glutathione reductase, while exhibiting elevated levels of malonyldialdehyde and activities of superoxide dismutase, glutathione transferase, and catalase. Finally, creatinine clearing was found to be correlated (p < 0.001) to total (oxidized and reduced) gluta-thione, Gpx and MDA. These observations may serve to establish a simple protocol for evaluation of renal function.

Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia ( p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px ( r = .65, p < .001), selenium ( r = .47, p < .001), and GSH ( r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.