title: Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure.
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.
authors: Institute of Pediatrics, University of Foggia, Viale Pinto 1 O.O.R.R., Foggia, Italy.
authors: Maria
authors: M
authors: D'Apolito
authors: Xueliang
authors: X
authors: Du
authors: Haihong
authors: H
authors: Zong
authors: Alessandra
authors: A
authors: Catucci
authors: Luigi
authors: L
authors: Maiuri
authors: Tiziana
authors: T
authors: Trivisano
authors: Massimo
authors: M
authors: Pettoello-Mantovani
authors: Angelo
authors: A
authors: Campanozzi
authors: Valeria
authors: V
authors: Raia
authors: Jeffrey E
authors: JE
authors: Pessin
authors: Michael
authors: M
authors: Brownlee
authors: Ida
authors: I
authors: Giardino
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D052243:Resistin / Q000097:blood; D054839:Retinol-Binding Proteins, Plasma / Q000032:analysis; D014508:Urea / Q000097:blood*
chemical_list: D001786:Blood Glucose; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C502487:Rbp4 protein, mouse; D017382:Reactive Oxygen Species; D052243:Resistin; D054839:Retinol-Binding Proteins, Plasma; C499623:Retn protein, mouse; D014508:Urea; D005947:Glucose