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.

Download full-text


Available from: Massimo Mantovani, Jan 27, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Toxicological and Environmental Chemistry 01/2012; 94(6):1164-1174. DOI:10.1080/02772248.2012.686175 · 0.72 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents and characterizes the performance of complexity reduction techniques applied to optimum soft output demodulation algorithms for a general modulation model. The optimum soft output algorithm (OSA) recursively computes the posterior probability mass function (PMF) of the modulation state and each information symbol conditioned on the modulation state up to a decoding lag of K. The recursion has complexity O(||σ<sub>k</sub>||M<sup>2</sup>K) where ||σ<sub>k</sub>|| is the cardinality of the modulation state and M is the cardinality of the information symbols. This paper focuses on two complexity reduction techniques: (1) retaining states in the OSA recursion only if their PMF is above a threshold (T-OSA) and (2) a reduced state version of OSA (RSSOA) where demodulation occurs assuming a modulation state of lower cardinality than the true modulation state. These algorithms greatly reduce the complexity of OSA while in many cases retaining near optimum performance. Examples are considered for known intersymbol interference channels, concatenated convolution codes, and continuous phase modulation
    Global Telecommunications Conference, 1996. GLOBECOM '96. 'Communications: The Key to Global Prosperity; 12/1996
Show more