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: 15.39). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1(-/-) mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.
    Proceedings of the National Academy of Sciences 02/2014; · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A major challenge for a wearable dialysis device is removal of urea, as urea is difficult to adsorb while daily production is very high. Electro-oxidation (EO) seems attractive because electrodes are durable, small, and inexpensive. We studied the efficacy of urea oxidation, generation of chlorine by-products, and their removal by activated carbon (AC). EO units were designed. Three electrode materials (platinum, ruthenium oxide, and graphite) were compared in single pass experiments using urea in saline solution. Chlorine removal by AC in series with EO by graphite electrodes was tested. Finally, urea-spiked bovine blood was dialyzed and dialysate was recirculated in a dialysate circuit with AC in series with an EO unit containing graphite electrodes. Platinum electrodes degraded more urea (21 ± 2 mmol/h) than ruthenium oxide (13 ± 2 mmol/h) or graphite electrodes (13 ± 1 mmol/h). Chlorine generation was much lower with graphite (13 ± 4 mg/h) than with platinum (231 ± 22 mg/h) or ruthenium oxide electrodes (129 ± 12 mg/h). Platinum and ruthenium oxide electrodes released platinum (4.1 [3.9–8.1] umol/h) and ruthenium (83 [77–107] nmol/h), respectively. AC potently reduced dialysate chlorine levels to <0.10 mg/L. Urea was removed from blood by EO at constant rate (9.5 ± 1.0 mmol/h). EO by graphite electrodes combined with AC shows promising urea removal and chlorine release complying with Association for the Advancement of Medical Instrumentation standards, and may be worth further exploring for dialysate regeneration in a wearable system.
    Artificial Organs 05/2014; · 1.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the early 17 hundreds, a substance ultimately identified as urea was for the first time reported in urine. About a century later, in 1828, Whöler achieved the synthesis of this organic compound thus giving rise to modern organic chemistry. In parallel, physicians demonstrated that urine comes from the kidneys and contains large amounts of urea, which is produced outside of the kidneys establishing the humoral approach of renal physiology. Urea was the first uremic retention solute to be identified and it has been used as a marker of renal disease ever since. However, progress in the knowledge of urea metabolism has shown that it is susceptible to many extra-renal variations and therefore, it cannot be a reliable marker of renal function. It reflects protein intake in the stable patient and has been used to assess nutrition and dialysis efficacy in renal patients. While having been studied for almost 200 years, its toxicity has been largely debated. An indirect toxicity occurring through carbamylation of lysine residues is now well established and some evidence from recent work also supports a direct toxicity of urea, offering additional rationale for interventional prevention of uremic complications.
    Seminars in Nephrology 01/2014; · 2.83 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014

Similar Publications