Zuo Linhui, Qu Minli, Zhang Mengru, Cheng Peng, Guo Min, Selvarajah Dinesh, Tesfaye Solomon, Wu Jing
Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Hepatopathy and Endocrinology, The Affiliated Children's Hospital of Xiangya School of Medicine , Central South University (Hunan Children's Hospital), Changsha, Hunan, China.
Acta Diabetol. 2025 Jul 2. doi: 10.1007/s00592-025-02553-9.
Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. The increased apoptosis of Schwann cells (SCs) induced by high glucose (HG) is significant in the pathogenesis of DPN, but the mechanism remains unclear. Diacylglycerol kinase eta (Dgkh) is a member of the diacylglycerol kinases (DGKs) family that participates in glucose uptake, utilization, and energy homeostasis. But its role in DPN has not been reported.
Streptozotocin (STZ)-induced SD rats were used as an animal model of DPN and human Schwann cells (HSCs) were used as an in vitro model of simulated HG conditions. Behavioral tests, histopathology, the mRNA and protein expression levels were detected in vivo. Further, Dgkh was knocked down in vitro, and PKC-α agonist PMA and inhibitor Ro 31-8220 were added to HSCs to observe the effect of Dgkh/PKC-α on HSCs apoptosis.
The mechanical and thermal pain thresholds were significantly decreased in DPN rats induced by STZ. The increased apoptosis of the sciatic nerve in STZ-induced DPN rats is accompanied by the upregulation of Dgkh expression. HG leads to increased HSCs apoptosis by Dgkh increased expression. Meanwhile, the knockdown of Dgkh significantly improved HSCs apoptosis induced by HG. PMA effectively improved apoptosis in HG-induced HSCs, but did not affect Dgkh expression. And we discovered that the apoptosis of HSCs reversed by Dgkh knockdown vanished when the PKC-α inhibitor Ro 31-8220 was added.
Dgkh expression increased under HG conditions and triggered apoptosis of HSCs, boosting DPN via inhibiting PKC-α.
糖尿病周围神经病变（DPN）是糖尿病最常见的慢性并发症之一。高糖（HG）诱导的雪旺细胞（SCs）凋亡增加在DPN发病机制中具有重要意义，但其机制仍不清楚。二酰基甘油激酶η（Dgkh）是二酰基甘油激酶（DGKs）家族的成员，参与葡萄糖摄取、利用和能量稳态。但其在DPN中的作用尚未见报道。
将链脲佐菌素（STZ）诱导的SD大鼠作为DPN动物模型，将人雪旺细胞（HSCs）作为模拟HG条件的体外模型。在体内检测行为学测试、组织病理学、mRNA和蛋白表达水平。此外，在体外敲低Dgkh，并向HSCs中添加PKC-α激动剂PMA和抑制剂Ro 31-8220，以观察Dgkh/PKC-α对HSCs凋亡的影响。
STZ诱导的DPN大鼠的机械和热痛阈值显著降低。STZ诱导的DPN大鼠坐骨神经凋亡增加伴随着Dgkh表达上调。HG通过Dgkh表达增加导致HSCs凋亡增加。同时，敲低Dgkh显著改善了HG诱导的HSCs凋亡。PMA有效改善了HG诱导的HSCs凋亡，但不影响Dgkh表达。并且我们发现，当添加PKC-α抑制剂Ro 31-8220时，敲低Dgkh逆转的HSCs凋亡消失。
HG条件下Dgkh表达增加并触发HSCs凋亡，通过抑制PKC-α促进DPN。
