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Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure

Institute of Pediatrics, University of Foggia, Viale Pinto 1 O.O.R.R., Foggia, Italy.
The Journal of clinical investigation (Impact Factor: 13.77). 12/2009; 120(1):203-13. DOI: 10.1172/JCI37672
Source: PubMed

ABSTRACT 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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    • "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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