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Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin.

Authors: Schaefer, L  Tsalastra, W  Babelova, A  Baliova, M  Minnerup, J  Sorokin, L  Grone, HJ  Reinhardt, DP  Pfeilschifter, J  Iozzo, RV  Schaefer, RM 
Citation: Schaefer L, etal., Am J Pathol. 2007 Jan;170(1):301-15.
Pubmed: (View Article at PubMed) PMID:17200203
DOI: Full-text: DOI:10.2353/ajpath.2007.060497

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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CRRD Object Information
CRRD ID: 7365047
Created: 2013-10-16
Species: All species
Last Modified: 2013-10-16
Status: ACTIVE


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