title: Hyperglycemia triggers abnormal signaling and proliferative responses in Schwann cells.
abstract: Peripheral neuropathy is a serious diabetic complication. Delayed nerve regeneration in diabetic animal models suggests abnormalities in proliferation/differentiation of Schwann cells (SC). We recently reported that endothelins (ETs) regulate proliferation and phenotype in primary and immortalized SC (iSC). We now investigated changes in the effects of ETs on SC proliferation and signaling in nerve segments from streptozotocin-induced diabetic rats and in iSC exposed to high glucose. Cultured explants from diabetic rats displayed a delay in the time-course of [3H]-thymidine incorporation as well as enhanced sensitivity to endothelin-1 (ET-1) or insulin. iSC cultured in high (25 mM) glucose-containing media also exhibited higher [3H]-thymidine incorporation, along with an enhanced activation of p38 mitogen-activated protein kinase and phospholipase C in response to ET-1 or platelet-derived growth factor as compared to controls (5.5 mM glucose). These studies support an extra-vascular role of ETs in peripheral nerves and SC. The increased sensitivity to ET-1 in nerves and iSC exposed to high glucose may contribute to abnormal SC proliferation characterizing diabetic neuropathy.
authors.affiliation: Division of Hypertension, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Khaldoun
authors.initials: K
authors.lastname: Almhanna
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Wilkins
authors.forename: James R
authors.initials: JR
authors.lastname: Bavis
authors.forename: Subash
authors.initials: S
authors.lastname: Harwalkar
authors.forename: Liliana N
authors.initials: LN
authors.lastname: Berti-Mattera
mesh_terms: D000818:Animals; D002455:Cell Division; D003470:Culture Media; D046508:Culture Techniques; D004261:DNA Replication; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D003470:Culture Media; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D005947:Glucose; D013936:Thymidine