Diabetes
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
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 PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Thallas-Bonke, V.
Right arrow Articles by Forbes, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thallas-Bonke, V.
Right arrow Articles by Forbes, J. M.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Diabetes 53:2921-2930, 2004
© 2004 by the American Diabetes Association, Inc.

Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-{alpha}–Dependent Pathway

Vicki Thallas-Bonke1,2, Carsten Lindschau3, Bishoy Rizkalla1, Leon A. Bach2, Geoffrey Boner1,4, Matthias Meier3, Hermann Haller3, Mark E. Cooper1,2, and Josephine M. Forbes1,2

1 Danielle Alberti Memorial Centre for Diabetes Complications, Vascular Division, Wynn Domain, Baker Medical Research Institute, Melbourne, Australia
2 Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia
3 Department of Nephrology, Hannover Medical School, Hannover, Germany
4 Department of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-{alpha} as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-{alpha}. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-{alpha} as well as in the -ßI, -ßII, and -{varepsilon} isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-{alpha} from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-{alpha}, in the diabetic kidney, which can be directly inhibited by ALT-711.

Address correspondence and reprint requests to Vicki Thallas-Bonke, Diabetes Complications, Vascular Division, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne, Australia. E-mail: vicki.thallas{at}baker.edu.au


Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.