Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin.
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.
Schaefer
Liliana
L
Departments of Internal Medicine D, University of Münster, Münster, Germany. schaefer@med.uni-frankfurt.de
Tsalastra
Wasiliki
W
Babelova
Andrea
A
Baliova
Martina
M
Minnerup
Jens
J
Sorokin
Lydia
L
Gröne
Hermann-Josef
HJ
Reinhardt
Dieter P
DP
Pfeilschifter
Josef
J
Iozzo
Renato V
RV
Schaefer
Roland M
RM
D000818:Animals; D002478:Cells, Cultured; D058575:Decorin; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism* / Q000494:pharmacology; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000096:biosynthesis*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D054392:Adipokines
D058575:Decorin; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D011494:Protein Kinases; D011509:Proteoglycans; D017526:Receptor, IGF Type 1; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546878:DCN protein, human; C546879:Dcn protein, mouse; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C000605725:Fbn1 protein, rat; C546842:MTOR protein, human; C546843:mTOR protein, mouse