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

Am J Pathol. 2007 Jan;170(1):301-15. doi: 10.2353/ajpath.2007.060497.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Decorin
  • Diabetes Mellitus, Type 1 / metabolism
  • Extracellular Matrix Proteins / metabolism*
  • Extracellular Matrix Proteins / pharmacology
  • Fibrillin-1
  • Fibrillins
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Immunohistochemistry
  • Kidney / cytology
  • Kidney / metabolism*
  • Kidney Diseases / etiology
  • Kidney Diseases / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / biosynthesis*
  • Protein Binding
  • Protein Kinases / metabolism*
  • Proteoglycans / metabolism*
  • Proteoglycans / pharmacology
  • Rats
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • DCN protein, human
  • Dcn protein, mouse
  • Decorin
  • Extracellular Matrix Proteins
  • FBN1 protein, human
  • Fbn1 protein, mouse
  • Fbn1 protein, rat
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • Proteoglycans
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Receptor, IGF Type 1
  • Sirolimus