title: Nerve growth factor blocks the glucose-induced down-regulation of caveolin-1 expression in Schwann cells via p75 neurotrophin receptor signaling.
abstract: Altered neurotrophism in diabetic peripheral neuropathy (DPN) is associated in part with substantial degenerative changes in Schwann cells (SCs) and an increased expression of the p75 neurotrophin receptor (p75NTR). Caveolin-1 (Cav-1) is highly expressed in adult SCs, and changes in its expression can regulate signaling through Erb B2, a co-receptor that mediates the effects of neuregulins in promoting SC growth and differentiation. We examined the hypothesis that hyperglycemia-induced changes in Cav-1 expression and p75NTR signaling may contribute to altered neurotrophism in DPN by modulating SC responses to neuregulins. In an animal model of type 1 diabetes, hyperglycemia induced a progressive decrease of Cav-1 in SCs of sciatic nerve that was reversed by insulin therapy. Treatment of primary neonatal SCs with 20-30 mm d-glucose, but not l-glucose, was sufficient to inhibit transcription from the Cav-1 promoter and decrease Cav-1 mRNA and protein expression. Hyperglycemia prolonged the kinetics of Erb B2 phosphorylation and significantly enhanced the mitogenic response of SCs to neuregulin1-beta1, and this effect was mimicked by the forced down-regulation of Cav-1. Intriguingly, nerve growth factor antagonized the enhanced mitogenic response of SCs to neuregulin1-beta1 and inhibited the glucose-induced down-regulation of Cav-1 transcription, mRNA, and protein expression through p75NTR-dependent activation of JNK. Our data suggest that Cav-1 down-regulation may contribute to altered neurotrophism in DPN by enhancing the response of SCs to neuregulins and that p75NTR-mediated JNK activation may provide a mechanism for the neurotrophic modulation of hyperglycemic stress.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Tan
authors.forename: Shefali
authors.initials: S
authors.lastname: Rouen
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Barkus
authors.forename: Yelena S
authors.initials: YS
authors.lastname: Dremina
authors.forename: Dongwei
authors.initials: D
authors.lastname: Hui
authors.forename: Julie A
authors.initials: JA
authors.lastname: Christianson
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Wright
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Yoon
authors.forename: Rick T
authors.initials: RT
authors.lastname: Dobrowsky
mesh_terms: D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D012016:Reference Values; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001786:Blood Glucose; C495541:Cav1 protein, mouse; C495537:Cav1 protein, rat; D051242:Caveolin 1; D022461:Caveolins; D017931:DNA Primers; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D005947:Glucose