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

Abstract

The mechanism/s leading to diabetic neuropathy are complex. Transforming growth factor-β1 (TGF-β1) has been associated with diabetic nephropathy and retinopathy but not neuropathy. In this study, changes in TGF-β 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-β1 and TGF-β2 mRNA, but not TGF-β3, was increased at 4 and 12 weeks. In sciatic nerve TGF-β3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-β formed homoand heterodimers, of which β 2 /β 3 , β 1 /β 1 , and β 1 /β 3 were significantly increased, while that of the TGF-β 2 /β 2 homodimer was decreased, in diabetic compared to non-diabetic rats. In-vitro, pretreatment of embryonic DRG with TGF-β neutralizing antibody prevents the increase in total TGF-β protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-β2 > β1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-β neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in diabetic DRG and nerve, TGF-β isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-β neutralizing antibody. These findings implicate upregulation of TGF-β 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.

Ameliorative Effect and Underlying Mechanisms of Total Triterpenoids from <i>Psidium guajava</i> Linn (Myrtaceae) Leaf on High-Fat Streptozotocin-induced Diabetic Peripheral Neuropathy in Rats

“…All procedures were carried out in accordance with the principles of U.S. National Institutes of Health guidelines [10]. All study protocols were approved by the local government committee for animal research (approval ref no.…”

Microvascular Reactivity and Inflammatory Cytokines in Painful and Painless Peripheral Diabetic Neuropathy

“…Each symptom was scored with one point if it was present and two points if nocturnal exacerbation was also present. A score of four or more points was considered to be abnormal (4,11). For the evaluation of the clinical signs of peripheral diabetic neuropathy, the sensations of pain, touch, cold, and vibration were tested in both legs of all patients.…”

“…For the evaluation of the clinical signs of peripheral diabetic neuropathy, the sensations of pain, touch, cold, and vibration were tested in both legs of all patients. A NDS more than five was considered to be abnormal (4,11).…”

“…In addition, numerous growth factors, such as vascular endothelial growth factor (VEGF), nerve growth factor, and TGF␤, have also been implicated in the pathogenesis of diabetic neuropathy and have been targeted as possible new therapeutic approaches (3,4). However, an additional problem is that all the above information is based on animal studies and very little information is available regarding human diabetes.…”

Cell Therapy for Diabetic Retinopathy—A Work in Progress

“…50,51 However, the serum levels and perhaps even the intracellular levels of TGF-β in EPCs are elevated in diabetes, and it has been proposed that this could be one of the mechanisms whereby chronic hyperglycemia causes cellular injury by promoting cellular senescence and growth arrest. 52,53 In general, then, it begs the question, do elevated TGF-β levels in diabetes contribute to EPC dysfunctionality, but also can these levels be reduced to more physiological levels and will this permit the return to EPC functional normality and consequently normal vascular repair in the retina? with activation of these receptors with stromal-derived factor-1 (SDF-1), leading to increased nitric oxide production.…”