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PMID:18406405

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Citation

Anjaneyulu, M, Berent-Spillson, A, Inoue, T, Choi, J, Cherian, K and Russell, JW (2008) Transforming growth factor-beta induces cellular injury in experimental diabetic neuropathy. Exp. Neurol. 211:469-79

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.

Links

PubMed PMC2453508 Online version:10.1016/j.expneurol.2008.02.011

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:TGFB1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:69051

F

Seeded From UniProt

complete

RAT:TGFB1

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:TGFB2

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:70491

F

Seeded From UniProt

complete

RAT:TGFB2

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:TGFB3

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:TGFB3

enables

GO:0046982: protein heterodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:TGFB1

enables

GO:0042803: protein homodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:TGFB1

enables

GO:0046982: protein heterodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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