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J. Biol. Chem., Vol. 278, Issue 25, 23151-23162, June 20, 2003

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Nerve Growth Factor Blocks the Glucose-induced Down-regulation of Caveolin-1 Expression in Schwann Cells via p75 Neurotrophin Receptor Signaling^*

Wenbin Tan, Shefali Rouen, Kristin M. Barkus, Yelena S. Dremina, Dongwei Hui, Julie A. Christianson , Douglas E. Wright , Sung Ok Yoon  and Rick T. Dobrowsky ¶

From the Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, the Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, and the Neurobiotech Center and Department of Biochemistry, Ohio State University, Columbus, Ohio 43210

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 (p75^NTR). 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 p75^NTR 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 neuregulin1-1, 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 neuregulin1-1 and inhibited the glucose-induced down-regulation of Cav-1 transcription, mRNA, and protein expression through p75^NTR-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 p75^NTR-mediated JNK activation may provide a mechanism for the neurotrophic modulation of hyperglycemic stress.

Received for publication, December 19, 2002 , and in revised form, March 11, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF489529.

^* This work was supported by National Institutes of Health Grants NS38154 and DK59749 (to R. T. D.), Grant DK59749 was co-sponsored by the National Institute of Diabetes, Digestive and Kidney Diseases, the National Institute of Neurologic Disorders and Stroke, and the Juvenile Diabetes Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, University of Kansas, 5064 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045. Tel.: 785-864-3531; Fax: 785-864-5219; E-mail: dobrowsky{at}ku.edu.

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