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Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure
Maria D’Apolito, … , Michael Brownlee, Ida Giardino
Maria D’Apolito, … , Michael Brownlee, Ida Giardino
Published December 1, 2009
Citation Information: J Clin Invest. 2010;120(1):203-213. https://doi.org/10.1172/JCI37672.
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Research Article

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

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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 β-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

Maria D’Apolito, Xueliang Du, Haihong Zong, Alessandra Catucci, Luigi Maiuri, Tiziana Trivisano, Massimo Pettoello-Mantovani, Angelo Campanozzi, Valeria Raia, Jeffrey E. Pessin, Michael Brownlee, Ida Giardino

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Figure 10

Treatment of uremic mice with a SOD/catalase mimetic normalizes insulin resistance–associated adipokine levels in adipose tissue and in plasma.

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Treatment of uremic mice with a SOD/catalase mimetic normalizes insulin ...
Treated uremic mice and treated controls received MnTBAP i.p. for 2 weeks. (A) Relative expression of RBP4 and resistin in epididymal adipose tissue of untreated and MnTBAP-treated control and uremic mice measured by qPCR. The control values are shown as 1.0. (B) Plasma levels of RBP4 and resistin measured in the plasma of the untreated and MnTBAP-treated control mice and in the plasma of untreated and MnTBAP-treated CRF mice by semiquantitative Western blot or ELISA, respectively. Each bar represents the mean ± SEM of 7 mice per group. *P < 0.01 compared with controls.

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