help button home button Am J Pathol R & D Systems
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
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 reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schaefer, L.
Right arrow Articles by Schaefer, R. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schaefer, L.
Right arrow Articles by Schaefer, R. M.
(American Journal of Pathology. 2007;170:301-315.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060497

Decorin-Mediated Regulation of Fibrillin-1 in the Kidney Involves the Insulin-Like Growth Factor-I Receptor and Mammalian Target of Rapamycin

Liliana Schaefer*{ddagger}, Wasiliki Tsalastra*, Andrea Babelova*, Martina Baliova*, Jens Minnerup*, Lydia Sorokin{dagger}, Hermann-Josef Gröne§, Dieter P. Reinhardt, Josef Pfeilschifter{ddagger}, Renato V. Iozzo|| and Roland M. Schaefer*

From the Departments of Internal Medicine D,* and Physiological Chemistry and Pathobiochemistry,{dagger} University of Münster, Münster, Germany; Pharmazentrum Frankfurt,{ddagger} Institut fur Allgemeine Pharmakologie und Toxikologie/Zentrum für Arzneimittelsicherheit, Entwicklung und Sicherheit, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany; the Department of Cellular and Molecular Pathology,§ German Cancer Research Center, Heidelberg, Germany; the Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; and the Department of Pathology,|| Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania

Decorin, a small leucine-rich proteoglycan, affects the synthesis of the elastic fiber component fibrillin-1 in the kidney via hitherto unknown mechanisms. Here, we show that decorin binds to and induces phosphorylation of insulin-like growth factor-I (IGF-I) receptor in renal fibroblasts. Inhibition of the IGF-I receptor tyrosine kinase and its downstream target phosphoinositide-3 kinase prevented decorin-mediated synthesis of fibrillin-1. Furthermore, decorin induced phosphorylation of phosphoinositide-dependent kinase 1, protein kinase B/Akt, mammalian target of rapamycin (mTOR), and p70 S6 kinase. Accordingly, the enhanced synthesis of fibrillin-1 was blocked by rapamycin, an inhibitor of mTOR. Notably, IGF-I, which signals through the same pathway, also stimulated fibrillin-1 synthesis. Systemic administration of rapamycin to mice subjected to unilateral ureteral obstruction, a model of renal fibrosis and increased fibrillin-1 synthesis, markedly reduced the number of interstitial fibroblasts and fibrillin-1 deposition. In streptozotocin-induced diabetes, IGF-I receptor was up-regulated in the kidneys from decorin-null mice. However, this could not compensate for the decorin deficiency, resulting ultimately in decreased fibrillin-1 content. This study provides evidence for the involvement of decorin and the IGF-I receptor/mTOR/p70 S6 kinase signaling pathway in the translational regulation of fibrillin-1.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2007 by the American Society for Investigative Pathology.