Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF | Erratum | Addendum
Research Article Article has an altmetric score of 9

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

  • Text
  • PDF
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

×

Figure 5

Urea-induced ROS increase IRS-1 modification by O-GlcNAc in 3T3L1 adipocytes.

Options: View larger image (or click on image) Download as PowerPoint
Urea-induced ROS increase IRS-1 modification by O-GlcNAc in 3T3L1 adipoc...
(A) IP Western blot analysis of IRS-1 modification by O-GlcNAc in urea-treated 3T3L1 cells (48 hours) and their controls. (B) IP Western blot analysis of IRS-1 modification by O-GlcNAc in urea-treated 3T3-L1 cells alone and after overexpression of catalase, UCP1, and MnSOD. Cells were infected with adenoviral vectors expressing catalase, UCP1, or MnSOD. After incubation with urea for 48 hours, IRS-1 was immunoprecipitated and the amount of O-GlcNAc modification was analyzed by immunoblotting. Levels of modification in cells infected with empty vector are shown as 100% in bar graphs. n = 5; *P < 0.01 compared with controls. Data represent mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Posted by 1 X users
Mentioned by 1 peer review sites
139 readers on Mendeley
1 readers on CiteULike
See more details