D'Apolito, M. et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J. Clin. Invest. 120, 203-213

Institute of Pediatrics, University of Foggia, Viale Pinto 1 O.O.R.R., Foggia, Italy.
The Journal of clinical investigation (Impact Factor: 13.22). 12/2009; 120(1):203-13. DOI: 10.1172/JCI37672
Source: PubMed


Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased expression of adipokines retinol binding protein 4 (RBP4) and resistin, and increased O-GlcNAc-modified insulin signaling molecules. Investigation of a mouse model of surgically induced renal failure (uremic mice) revealed increased ROS production, modification of insulin signaling molecules by O-GlcNAc, and increased expression of RBP4 and resistin in visceral adipose tissue. Uremic mice also displayed insulin resistance and glucose intolerance, and treatment with an antioxidant SOD/catalase mimetic normalized these defects. The SOD/catalase mimetic treatment also prevented the development of insulin resistance in normal mice after urea infusion. These data suggest that therapeutic targeting of urea-induced ROS may help reduce the high morbidity and mortality caused by end-stage renal disease.

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Available from: Massimo Mantovani, Jan 27, 2014
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    • "Reduced creatinine clearance has been reported in 8 week-old (young) ApoE-/- mice [14] indicating some degree of vulnerability in glomerular filtration. Oxidative stress is associated with either high uremia levels or methanol ocurrence in blood [15]. In L mice uremic toxicity and increased oxidative stress may correlate with a pro-inflammatory condition. "
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    ABSTRACT: Background Atherosclerosis is a major health burden. Metabolic disorders had been associated with large consumption of soft drinks. The rising incidence of atherosclerosis and metabolic alterations warrants the study of long-term soft drink consumption’ effects on metabolism and atherosclerosis in genetic deficiency of apolipoprotein E which typically develops spontaneous atherosclerosis and metabolic alterations. Methods ApoE-/- mice were randomized in 3 groups accordingly with free access to: water (W), regular cola (C) or light cola (L). After 8 weeks, 50% of the animals in each group were euthanized (Treatment: W8, C8, L8). The remaining mice (all groups) drank water for 8 weeks and were euthanized (Washout: W16, C16, L16). Body weight and food and drink consumption were periodically measured. Blood was collected (biochemistry). At autopsy, transverse aortic sinus sections were serially cut and stained (histomorphometry); livers and kidneys were processed (microscopy). MANOVA (identification of variance factors) was followed by ANOVA and LSD tests (within-factor differences between levels). Conventionally a p< 0.05 was considered significant. Results Treatment increased drinking volumes (vs W8: 4 fold C8, p<0.0001; +47% L8, p<0.02). Only C reduced eating amounts (–54%, p<0.05 vs W8). I). Compared with W8: C8 developed hyperglycemia (+43%, p<0.03) and increased non-HDL cholesterol (+54%, p<0.05); L8 showed decreased glycemia (–15%, p<0.05 vs W8) and increased creatinine (2.5 fold, p<0.04), urea (+74, p<0.03) and aspartate-aminotransferase (2.8 fold, p<0.05). Hypercreatininemia was observed in L16 (2.7 fold vs W16, p<0.05). Hypertriglyceridemia (+91%, p<0.008) and hyperuremia (+68%, p<0.03) developed over time of study (age). II). Treatment caused plaque area increase (vs W8: 28% C8, p<0.02 and 50% L8, p<0.01; vs W16: 43% C16, p<0.05 and 68% L16, p<0.02) and stenosis (vs W8: 38% C8, p<0.04 and 57% L8, p<0.01; vs W16: 71% C16, p<0.01 and 46% L16, p<0.04). Age also caused plaque area increase (56%, p<0.04). Treatment- and age-effects on plaque enlargement were additive. Conclusion Cola beverages caused atherosclerotic lesions’ enlargement with metabolic (C) or non metabolic disturbances (L). ApoE-/- mice were particularly sensitive to L treatment. These findings may likely relate to caramel colorant and non-nutritive sweeteners in cola drinks and have potential implications in particularly sensitive individuals.
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    • "Pseudouridine [65], which accumulates in the circulation, and asymmetric dimethyl arginine (ADMA) [114] are recognized as an important uremic toxins associated with CKD and IR. Urea, which was previously considered to have negligible toxicity, induced reactive oxygen species generation and caused IR in an animal model [115]. "
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    ABSTRACT: Metabolic syndrome and its components are associated with chronic kidney disease (CKD) development. Insulin resistance (IR) plays a central role in the metabolic syndrome and is associated with increased risk for CKD in nondiabetic patients. IR is common in patients with mild-to-moderate stage CKD, even when the glomerular filtration rate is within the normal range. IR, along with oxidative stress and inflammation, also promotes kidney disease. In patients with end stage renal disease, IR is an independent predictor of cardiovascular disease and is linked to protein energy wasting and malnutrition. Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. In addition to adequate renal replacement therapy and correction of uremia-associated factors, thiazolidinedione, ghrelin, protein restriction, and keto-acid supplementation are therapeutic options. Weight control, reduced daily prednisolone dosage, and the use of cyclosporin decrease the risk of developing new-onset diabetes after kidney transplantation. Improved understanding of the pathogenic mechanisms underlying IR in CKD may lead to more effective therapeutic strategies to reduce uremia-associated morbidity and mortality.
    Full-text · Article · Aug 2012 · BioMed Research International
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    • "Non-physiologic concentrations of urea were reported to increase the levels of reactive oxygen species (ROS) and the oxidative stress marker 8-oxoguanine in cultured IMCD3 cells (Zhang et al. 2004). D'Apolito et al. (2010) found that urea at a concentration of 20 mM elevated ROS levels in 3T3-L1 adipocytes by 2.9 fold, and treatment with a superoxide dismutase (SOD)/catalase mimetic prevented these urea-induced abnormalities. Inorganic mercury (Hg), a heavy metal, is highly toxic to both *Corresponding author. "
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    ABSTRACT: The present investigation examined the detoxifying potential of methanolic herbal extracts, namely the leaf and bark extract of Eucalyptus tereticornis, bark extract of Saraca asoca, Cassia fistula and Withania somnifera in vitro using primary chicken embryo fibroblast (CEF) cells against damaging effects of urea and mercuric chloride (HgCl) (II). The influence of 20mM urea and 10 mMHgCl (II) was determined on cell viability or proliferation of cells after treatment with plant extracts. Higher survival rate of primary CEF cells treated with higher concentrations of plant extracts was observed due to their protective ability against urea and HgCl (II). Cassia fistula bark extract (10 mgmL�1) was found to be most effective against 20mM urea as it protects 90% of CEF cells whereas W. somnifera protects 86% of the cells within 24 h. After treating cells with10 mM HgCl, W. somnifera and E. tereticornis leaf extracts were found to be more effective among all other extracts as they protect approximately 86% and 70% of CEF cells, respectively, within 24 h. These results indicate that C. fistula and W. somnifera has the highest potential amongst all the five plant extracts for protecting CEF cells against damaging effects of urea and HgCl (II), respectively.
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