Endoplasmic Reticulum Stress Plays a Key Role in the Pathogenesis of Diabetic Peripheral Neuropathy

Abstract

Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins impairs metabolism, transcriptional regulation, and gene expression, and it is a key mechanism of cell injury. Endoplasmic reticulum stress plays an important role in cardiovascular and neurodegenerative diseases, cancer, and diabetes. We evaluated the role for this phenomenon in diabetic peripheral neuropathy. Endoplasmic reticulum stress manifest in upregulation of multiple components of unfolded protein response was identified in neural tissues (sciatic nerve, spinal cord) of streptozotocin diabetic rats and mice. A chemical chaperone, trimethylamine oxide, administered for 12 weeks after induction of diabetes (110 mg⋅kg−1⋅d−1, a prevention paradigm) attenuated endoplasmic reticulum stress, peripheral nerve dysfunction, intraepidermal nerve fiber loss, and sciatic nerve and spinal cord oxidative-nitrative stress in streptozotocin diabetic rats. Similar effects on diabetes-induced endoplasmic reticulum stress and peripheral nerve dysfunction were observed with a structurally unrelated chemical chaperone, 4-phenylbutyric acid (100 mg⋅kg−1⋅d−1, intraperitoneal). CCAAT/enhancer-binding protein homologous protein (CHOP)−/− mice made diabetic with streptozotocin displayed less severe sciatic nerve oxidative-nitrative stress and peripheral neuropathy than the wild-type (C57Bl6/J) mice. Neither chemical chaperones nor CHOP gene deficiency reduced diabetic hyperglycemia. Our findings reveal an important role of endoplasmic reticulum stress in the development of diabetic peripheral neuropathy and identify a potential new therapeutic target.

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

“…The structures of compound 1 -5 were identified by comparing the 1 H NMR and 13 C NMR spectral data with previous literature reports. Principal components are shown in Table 1.…”

“…SNCV was measured in the digital nerve to the second toe, using the smallest intensity current that resulted in an amplitude response, and was recorded in meters per second as the ratio of distance between stimulating and recording electrodes. [12,13] To determine the thermal response latency, rats were placed within a plexi glass chamber and allowed to acclimatize for at least 20 min. A thermal stimulation meter from ChengDu Technology & Market Co., LTD. (Chengdu, China) was used.…”

Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury

“…46 Under stressful situations, the ER environment was compromised, and protein maturation was impaired. ER stress usually caused misfolded proteins to accumulate and triggered a characteristic stress response known as the unfolded protein response (UPR).…”

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…4-PBA-treated diabetic group (n = 12), treated with 100 mg/kg/d 4-PBA (Santa Cruz Biotechnology, CA, USA) in vehicle. 23,24 All mice were treated for 12 weeks.…”