Targeting Schwann-cell apoptosis in diabetes: The emerging role of Dgkh–PKC-α signaling

Aims: To investigate the role of diacylglycerol kinase-η (Dgkh) in Schwann-cell apoptosis and its involvement in the pathogenesis of diabetic peripheral neuropathy (DPN), particularly through modulation of the PKC-α signaling pathway.

Methods: The effects of hyperglycemia on Dgkh/PKC-α signaling and Schwann-cell apoptosis were studied in streptozotocin-induced diabetic rats and high-glucose-treated human Schwann cells. Neuropathy was assessed by behavioral testing and nerve histology; the expression of Dgkh, PKC-α, and apoptotic markers was analyzed by immunohistochemistry, qPCR, and Western blot. Functional relevance was tested using Dgkh knock-down and pharmacological modulation of PKC-α.

Results: STZ rats developed sustained hyperglycemia, weight loss, and progressive sensory loss (decreased thermal threshold and mechanical threshold). Sciatic nerves showed demyelination, axonal atrophy, and a higher proportion of TUNEL-positive cells (apoptotic cells), coinciding with up-regulation of Dgkh and down-regulation of PKC-α. High glucose increased Dgkh, Bax and active-caspase-3 while suppressing Bcl-2 in HSCs; cell viability fell significantly. Dgkh knock-down restored PKC-α, normalized Bax/Bcl-2, and reduced apoptosis. PMA (PKC-α agonist) mimicked the protective effect without altering Dgkh, whereas Ro 31-8220 (PKC-α inhibitor) eliminated the benefit of Dgkh knock-down, confirming that Dgkh acts upstream of PKC-α.

Conclusions: High glucose up-regulates Dgkh, which inhibits PKC-α, triggers Schwann-cell apoptosis and contributes to DPN. Targeting the Dgkh/PKC-α axis may offer a novel therapeutic strategy.

Comments: This study identifies a novel mechanism by which hyperglycemia promotes Schwann-cell apoptosis and contributes to DPN. In a STZ-induced diabetic rat model, the authors observed progressive sensory loss, and increased Schwann-cell apoptosis. These pathological changes were associated with upregulation of Dgkh and downregulation of PKC-α in sciatic nerves. Complementary in-vitro experiments using human Schwann cells exposed to high glucose replicated these findings. Dgkh expression increased alongside pro-apoptotic markers (Bax, caspase-3), while anti-apoptotic Bcl-2 decreased. Lentiviral knock-down of Dgkh restored PKC-α levels, reduced apoptosis, and improved cell viability. Pharmacological modulation confirmed that PKC-α acts downstream of Dgkh in this pathway. A key strength of the study is its translational design, integrating behavioral and histological evidence from the animal model with mechanistic experiments in human Schwann cells. The authors used both genetic and pharmacological tools to dissect signaling hierarchies, strengthening the conclusion that Dgkh is a key upstream regulator of Schwann-cell injury in diabetes. Limitations include the small animal sample size, use of only male rats, and the high glucose concentration (75 mM) used in vitro, which exceeds typical diabetic conditions. Moreover, potential roles of other PKC isoforms were not explored. Overall, the study proposes the Dgkh–PKC-α axis as a novel link between hyperglycemia and Schwann-cell apoptosis in DPN. While further validation is needed, particularly in in-vivo models with targeted Dgkh modulation, the findings suggest a promising new target for therapeutic intervention in diabetic neuropathy.

Zoltan Kender

Reference: Zuo L, Qu M, Zhang M, Cheng P, Guo M, Selvarajah D, Tesfaye S, Wu J. High glucose mediates diabetic peripheral neuropathy by inducing Schwann cells apoptosis through the Dgkh/PKC-α signaling pathway. Acta Diabetol. 2025 Jul 2. doi: 10.1007/s00592-025-02553-9. Epub ahead of print. PMID: 40600984.

🔗 https://link.springer.com/article/10.1007/s00592-025-02553-9