Roles of Neuronal Protein Kinase C ε on Endoplasmic Reticulum Stress and Autophagic Formation in Diabetic Neuropathy

AbstractIn chronic diabetic neuropathy (DN), the cellular mechanisms of neuropathic pain remain unclear. Protein kinase C epsilon (PKC ε) is an intracellular signaling molecule that mediates chronic pain. This paper addresses the long-term upregulated PKCε in DN associated with endoplasmic reticulum (ER) stress and autophagic formation and correlates to chronic neuropathic pain. We found that thermal hyperalgesia and mechanical a llodynia course development were associated with PKCε upregulation after DN but not skin denervation. Pathologically, PKCε upregulation was associated with the expression of inositol-requiring enzyme 1α (IRE1α; ER stress–related molecule) and ubiquitin D (UBD), which are involved in the ubiqui tin-proteasome system (UPS)-mediated degradation of misfolded proteins under ER stress. Manders coefficient analyses revealed an approximately 50% colocalized ratio for IRE1α(+):PKCε(+) neurons (0.34–0.48 for M1 and 0.40–0.58 for M2 Manders coefficients). The colocalized coefficients of UBD/PK Cε increased (M1: 0.33 ± 0.03 vs. 0.77 ± 0.04, p <  0.001; M2: 0.29 ± 0.05 vs. 0.78 ± 0.04; p <  0.001) in the acute DN stage. In addition, the regulatory subunit p85 of phosphoinositide 3-kinase, which is involved in regulating insulin signaling, exhibited similar expression patterns to those of IRE1α and UBD; for example, it had highly colocalized ratios to PKCε. The ultrastructural exam ination further confirmed that a...
Source: Molecular Neurobiology - Category: Neurology Source Type: research