Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure.
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.
D'Apolito
Maria
M
Institute of Pediatrics, University of Foggia, Viale Pinto 1 O.O.R.R., Foggia, Italy.
Du
Xueliang
X
Zong
Haihong
H
Catucci
Alessandra
A
Maiuri
Luigi
L
Trivisano
Tiziana
T
Pettoello-Mantovani
Massimo
M
Campanozzi
Angelo
A
Raia
Valeria
V
Pessin
Jeffrey E
JE
Brownlee
Michael
M
Giardino
Ida
I
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*
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