Transforming growth factor-beta induces cellular injury in experimental diabetic neuropathy

Exp Neurol. 2008 Jun;211(2):469-79. doi: 10.1016/j.expneurol.2008.02.011. Epub 2008 Mar 2.

Abstract

The mechanism/s leading to diabetic neuropathy are complex. Transforming growth factor-beta1 (TGF-beta1) has been associated with diabetic nephropathy and retinopathy but not neuropathy. In this study, changes in TGF-beta isoforms were examined in vivo and in vitro. Two groups of animals, streptozotocin diabetic with neuropathy and non-diabetic controls were examined at 4 weeks (n=10/group) and 12 weeks (n=8/group). In diabetic DRG using quantitative real-time PCR (QRT-PCR), TGF-beta1 and TGF-beta2 mRNA, but not TGF-beta3, was increased at 4 and 12 weeks. In sciatic nerve TGF-beta3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-beta formed homo- and hetero-dimers, of which beta(2)/beta(3), beta(1)/beta(1), and beta(1)/beta(3) were significantly increased, while that of the TGF-beta(2)/beta(2) homodimer was decreased, in diabetic compared to non-diabetic rats. In vitro, pretreatment of embryonic DRG with TGF-beta neutralizing antibody prevents the increase in total TGF-beta protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-beta2>beta1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-beta neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in diabetic DRG and nerve, TGF-beta isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-beta neutralizing antibody. These findings implicate upregulation of TGF-beta in experimental diabetic peripheral neuropathy and indicate a novel mechanism of cellular injury related to elevated glucose levels. In combination, these findings indicate a potential new target for treatment of diabetic peripheral neuropathy.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetic Neuropathies / genetics
  • Diabetic Neuropathies / metabolism*
  • Diabetic Neuropathies / pathology*
  • Gene Expression Regulation / physiology
  • Male
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1 / biosynthesis
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / physiology
  • Transforming Growth Factor beta2 / biosynthesis
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / physiology
  • Transforming Growth Factor beta3 / biosynthesis
  • Transforming Growth Factor beta3 / genetics
  • Transforming Growth Factor beta3 / physiology

Substances

  • Protein Isoforms
  • RNA, Messenger
  • Tgfb2 protein, rat
  • Tgfb3 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • Transforming Growth Factor beta3