CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Abstract

Background/Aims: Peripheral neuropathy is a frequent and severe diabetic complication characterized by progressive loss of peripheral nerve axons and manifested by pain and eventually complete loss of sensation. Effective therapy for diabetic peripheral neuropathy (DPN) is still lacking due to our limited understanding of the mechanisms for nerve injury. Methods: Here we tested the roles of endoplasmic reticulum (ER) stress and the ER stress-activated pro-apoptotic protein CHOP and anti-apoptotic protein ORP150 in DPN in a rat model of high-fat/streptozotocin diabetes and in cultured Schwann cells (SCs). Results: No significant DPN was seen in the early stage of diabetes (4 weeks following verification of diabetes). However, after prolonged diabetes (16 weeks following verification of diabetes), DPN was severely developed as reflected by slowed motor and sensory nerve conduction velocity, blunted thermal nociception, and decreased intraepidermal nerve fiber profiles in the hindpaw. Meanwhile, while it was not noticed in sciatic nerves of early diabetes, ER stress in prolonged diabetic rats was indicated by robust increases in H₂O₂ production and expression of the ER chaperon glucose-regulated protein 78 (GRP78). ORP150 expression was substantially upregulated, accompanied by mild increase in CHOP expression, resulting in a low CHOP/ORP150 ratio, in early diabetes. In contrast, with prolonged diabetes, CHOP expression exceeded ORP150 expression, resulting in an increased CHOP/ORP150 ratio. In vivo knockdown of ORP150 induced DPN in early diabetes and exacerbated the DPN after prolonged diabetes, whereas knockdown of CHOP ameliorated DPN in rats with prolonged diabetic. On the other hand, in vitro knockdown of ORP150 promoted high glucose-induced SC apoptosis, whereas knockdown of CHOP protected SCs from apoptosis. Conclusion: Taken together, we have provided evidence for the critical role of ER stress in the development of DN and also uncovered CHOP/ORP150 ratio as an important mechanism for determining neuronal apoptosis during ER stress. In the early stage of diabetes, CHOP/ORP150 ratio was relatively low favoring neuronal cell survival, whereas after prolonged diabetes, CHOP/ORP150 ratio increased resulting in apoptotic cell death leading to accelerated DPN.

Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus

“…Previously, it has been reported that due to the high mitochondrial density in Schwann cells, these cells are affected early by hyperglycemia and an oxidative environment in the diabetic condition, resulting in apoptosis ( Wu et al, 2013 ; Zhu et al, 2018 ). To analyze whether Schwann cells are susceptible to this noxious microenvironment during diabetes progression, we carried out a TUNEL assay in sciatic nerves, derived from diabetic and non-diabetic mice, and quantified the percentage of TUNEL + cells.…”

“…Previously, it has been reported that Schwann cells and neurons are highly susceptible to a diabetic microenvironment ( Delaney et al, 2001 ; Sango et al, 2006 ; Zhu et al, 2018 ); however, the nerve physiological consequences resulting from this cell injury are still unclear. Delaney and colleagues ( Delaney et al, 2001 ) demonstrated that hyperglycemia induces Schwann cells apoptosis in vitro and in vivo , but the proposed cellular mechanisms seem to be multifactorial and include hyperglycemia-dependent injury, endoplasmic reticulum stress, oxidative damage, polyol pathway overactivation, inflammation, growth factors depletion and hypoxia, among others ( Delaney et al, 2001 ; Sango et al, 2006 ; Dey et al, 2013 ; Misizin, 2014; Wu et al, 2013 ; Zhu et al, 2018 ). The results of our study showed evidence that Schwann cells become gradually more vulnerable to apoptosis as diabetes progresses; however, apoptotic cells were less than 3% of the total analyzed cell population.…”

Resveratrol exerts an anti-apoptotic effect on human bronchial epithelial cells undergoing cigarette smoke exposure

“…Oxygen-regulated protein 150 (ORP150) is an important member of the 70kDa heat shock protein family. Knockdown of ORP150 has previously been shown to promote endoplasmic reticulum (ER)-stress, induce apoptosis and increase the expression of CCAAT-enhancer binding protein (CHOP), an ER-stress-induced apoptosis marker ( 15 , 16 ). Jung et al ( 17 ) previously reported that through the induction of ORP150, SIRT1 alleviated palmitate-induced ER-stress in HepG2 human hepatocytes.…”

Peripheral neuropathy in a diabetic child treated with linezolid for multidrug-resistant tuberculosis: a case report and review of the literature

“…These pathological processes culminate in axonal atrophy with progressive demyelination, and neuronal apoptosis with decreased fibre regeneration. It is also possible that endoplasmic reticulum stress might contribute to diabetic peripheral neuropathy [5]. …”