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(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^*, Wasiliki Tsalastra^*, Andrea Babelova^*, Martina Baliova^*, Jens Minnerup^*, Lydia Sorokin, Hermann-Josef Gröne, Dieter P. Reinhardt^¶, Josef Pfeilschifter, Renato V. Iozzo^|| and Roland M. Schaefer^*

From the Departments of Internal Medicine D,^* and Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany; Pharmazentrum Frankfurt, 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.

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