Abstract
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM) and the dysfunction of Schwann cells plays an important role in the pathogenesis of DPN. Thioredoxin-interacting protein (TXNIP) is known as an inhibitor of thioredoxin and associated with oxidative stress and inflammation. However, whether TXNIP is involved in dysfunction of Schwann cells of DPN and the exact mechanism is still not known. In this study, we first reported that TXNIP expression was significantly increased in the sciatic nerves of diabetic mice, accompanied by abnormal electrophysiological indexes and myelin sheath structure. Similarly, in vitro cultured Schwann cells TXNIP was evidently enhanced by high glucose stimulation. Again, the function experiment found that knockdown of TXNIP in high glucose-treated RSC96 cells led to a 4.12 times increase of LC3-II/LC3-I ratio and a 25.94% decrease of cleaved caspase 3/total caspase 3 ratio. Then, DNA methyltransferase (DNMT) inhibitor 5-Aza has been reported to benefit Schwann cell in DPN, and here 5-Aza treatment reduced TXNIP protein expression, improved autophagy and inhibited apoptosis in high glucose-treated RSC96 cells and the sciatic nerves of diabetic mice. Furthermore, DNMT1 and DNMT3a upregulation were found to be involved in TXNIP overexpression in high glucose-stimulated RSC96 cells. Silencing of DNMT1 and DNMT3a effectively reversed high glucose-enhanced TXNIP. Moreover, high glucose-inhibited PI3K/Akt pathway led to DNMT1, DNMT3a, and TXNIP upregulation in RSC96 cells. Knockdown of DNMT1 and DNMT3a prevented PI3K/Akt pathway inhibition-caused TXNIP upregulation in RSC96 cells. Finally, in vivo knockout of TXNIP improved nerve conduction function, increased autophagosome and LC3 expression, and decreased cleaved Caspase 3 and Bax expression in diabetic mice. Taken together, PI3K/Akt pathway inhibition mediated high glucose-induced DNMT1 and DNMT3a overexpression, leading to cell autophagy inhibition and apoptosis via TXNIP protein upregulation in Schwann cells of DPN.
Highlights
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM) and has a variety of clinical manifestations including neuropathic pain, autonomic nerves system dysfunction, sensory loss, and diabetic foot
In the present study, we first found that Thioredoxin-interacting protein (TXNIP) expression was significantly increased in the Schwann cells of sciatic nerves in diabetic mice, in vitro cultured RSC96 cells, human Schwann cells (HSC) cells and primary rat Schwann cells (PRSC) cells
Cheng et al found that high glucose caused RSC96 cells viability loss, reactive oxygen species (ROS) generation, TXNIP expression, and NLRP3 inflammasome activation, followed by IL-1β and IL-18 maturation and gasdermin D cleavage [12]
Summary
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM) and has a variety of clinical manifestations including neuropathic pain, autonomic nerves system dysfunction, sensory loss, and diabetic foot. A better elucidation and understanding of the exact mechanism involved in the pathogenesis and development of DPN is necessary to find the promising approaches to treat this disease [1]. Schwann cell dysfunction was gradually realized in the pathogenesis of diabetic peripheral neuropathy. The accumulating data demonstrated that the metabolic disturbance of Schwann cells in diabetes mellitus (DM) caused neurotoxic intermediates accumulation and neurotrophic factors deficiency, in turn the damage of both the vasculature and axons, leading to DPN [2, 3]. The exact mechanism involved in Schwann cell dysfunction of DPN is still not known
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