AJP - Renal Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol (June 14, 2005). doi:10.1152/ajprenal.00094.2005
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/5/F1144    most recent
00094.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (12)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, S.
Right arrow Articles by Meggs, L. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, S.
Right arrow Articles by Meggs, L. G.
Submitted on March 9, 2005
Accepted on June 6, 2005

Activated IGF-1R Inhibits Hyperglycemia-Induced DNA Damage and Promotes DNA Repair by Homologous Recombination

Shuo Yang1, Janaki Chintapalli1, Lakshmi Sodagum2, Stuart Baskin2, Ashwani Malhotra2, Krzysztof Reiss1, and Leonard G. Meggs2*

1 Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, PA, USA
2 New Jersey Medical School, Department of Medicine, Division of Nephrology and Hypertension, University of Medicine and Dentistry, Newark, NJ, USA

* To whom correspondence should be addressed. E-mail: meggslg{at}umdnj.edu.

The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-stranded breaks (SSBs) and double-stranded breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia induced DNA damage. To determine if DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic induced ROS production and hyperglycemia induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or non-homologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly 2-fold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA (siRNA) experiments markedly decreased % of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA, by suppressing ROS and enhancing DNA repair by HRR.




This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
T. Iwasa, I. Okamoto, M. Suzuki, E. Hatashita, Y. Yamada, M. Fukuoka, K. Ono, and K. Nakagawa
Inhibition of Insulin-Like Growth Factor 1 Receptor by CP-751,871 Radiosensitizes Non-Small Cell Lung Cancer Cells
Clin. Cancer Res., August 15, 2009; 15(16): 5117 - 5125.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Malhotra, H. Vashistha, V. S. Yadav, M. G. Dube, S. P. Kalra, M. Abdellatif, and L. G. Meggs
Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis
Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H380 - H388.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
S. Dimmeler and A. Leri
Aging and Disease as Modifiers of Efficacy of Cell Therapy
Circ. Res., June 6, 2008; 102(11): 1319 - 1330.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
A. Gonzalez, M. Rota, D. Nurzynska, Y. Misao, J. Tillmanns, C. Ojaimi, M. E. Padin-Iruegas, P. Muller, G. Esposito, C. Bearzi, et al.
Activation of Cardiac Progenitor Cells Reverses the Failing Heart Senescent Phenotype and Prolongs Lifespan
Circ. Res., March 14, 2008; 102(5): 597 - 606.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Q. Yao, B. Weigel, and J. Kersey
Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51
Clin. Cancer Res., March 1, 2007; 13(5): 1591 - 1600.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
J. Chintapalli, S. Yang, D. Opawumi, S. R. Goyal, N. Shamsuddin, A. Malhotra, K. Reiss, and L. G. Meggs
Inhibition of wild-type p66ShcA in mesangial cells prevents glycooxidant-dependent FOXO3a regulation and promotes the survival phenotype
Am J Physiol Renal Physiol, February 1, 2007; 292(2): F523 - F530.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 1977 by the American Physiological Society.