The Akt/mTOR cascade mediates high glucose-induced reductions in BDNF via DNMT1 in Schwann cells in diabetic peripheral neuropathy.
Brain-derived neurotropic factor (BDNF) deficiency in Schwann cells plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). Little is known about the mechanism involved in BDNF downregulation in Schwann cells in DPN. In this study, we first confirmed downregulation of BDNF and neurotrophin 3 expression in the sciatic nerves of diabetic mice, which was accompanied by myelin sheath abnormalities. Moreover, in vitro, high glucose was revealed to cause downregulation of BDNF, but not neurotrophin 3, expression in RSC96 cells, which was accompanied by DNA hypermethylation of BDNF promoters I and II. DNMT1 was subsequently revealed to be enhanced at the mRNA and protein levels in high glucose-stimulated RSC96 cells, and inhibition of DNMT1 with 5-Aza treatment or shRNA vector transfection reversed high glucose-induced reductions in BDNF expression. Furthermore, the mTOR and upstream Akt pathways were indicated to mediate high glucose-induced DNMT1 and BDNF expression in RSC96 cells. Taken together, our results suggest that the Akt/mTOR cascade mediates high glucose-induced reductions in BDNF via DNMT1 in Schwann cells in DPN.
['Zhang|Cui-Hong|CH|', 'Lv|Xin|X|', 'Du|Wei|W|', 'Cheng|Mei-Juan|MJ|', 'Liu|Ya-Ping|YP|', 'Zhu|Lin|L|', 'Hao|Jun|J|']
D000818:Animals D019208:Brain-Derived Neurotrophic Factor D002478:Cells, Cultured D019175:DNA Methylation D003921:Diabetes Mellitus, Experimental D003929:Diabetic Neuropathies D015536:Down-Regulation D005786:Gene Expression Regulation D005947:Glucose D008297:Male D051379:Mice D020933:Neurotrophin 3 D011401:Promoter Regions, Genetic D051057:Proto-Oncogene Proteins c-akt D051381:Rats D012583:Schwann Cells D012584:Sciatic Nerve D013549:Sweetening Agents D058570:TOR Serine-Threonine Kinases
mTOR BDNF DNMT1 Schwann cell Diabetic peripheral neuropathy High glucose