AGEs通过MZF1下调Kv1.2通道表达在糖尿病胃内脏高敏感中的作用及机制研究

糖尿病胃轻瘫发病机制复杂，胃内脏高敏感为核心机制之一，但导致内脏高敏机制尚不明确。我们前期发现：糖基化终末产物（AGEs）抑制剂可上调背根神经节（DRG）Kv1.2通道表达，降低感觉神经元兴奋性，改善糖尿病胃内脏高敏感。新近研究报道：转录因子髓样锌指蛋白（MZF1）参与感觉神经元Kv1.2调控。我们前期还发现：AGEs上调DRG内MZF1表达，下调Kv1.2表达；干扰MZF1可逆转糖尿病DRG内Kv1.2表达下调。生物信息预测Kv1.2反义RNA启动子区有MZF1结合序列。我们推测：糖尿病时，DRG内MZF1经AGEs转录激活，通过与Kv1.2反义RNA启动子区结合，上调后者表达，从而间接下调Kv1.2表达，最终增加DRG兴奋性是糖尿病胃内脏高敏感的关键机制。本研究拟在动物、细胞和分子水平，阐明AGEs/MZF1/Kv1.2参与糖尿病胃内脏高敏感发生,并确定MZF1是其中最关键可干预靶点。

Gastric visceral hypersensitivity plays a key role in the pathogenesis of diabetic gastroparesis (DGP), but the mechanism is unknown. We found that inhibition of advanced glycation end products (AGEs) can improve gastric hypersensitivity by reducing sensory neuron excitability. It was reported that myeloid zinc finger protein (MZF1) is involved in the regulation of Kv1.2 channels in sensory neurons. We also found that AGEs up-regulated MZF1 expression and down-regulated Kv1.2 expression in DRG. Furthermore, down-regulation of MZF1 expression inhibited Kv1.2 antisense RNA synthesis and reversed the down-regulation of Kv1.2 expression in diabetes. Therefore, we speculate that AGEs up-regulate the expression of MZF1 in DRG, and regulate Kv1.2 expression through Kv1.2 antisense RNA indirectly, thereby increasing DRG excitability. This study intends to elucidate the involvement of AGEs/MZF1/Kv1.2 in the diabetes-induced gastric hypersensitivity from the animal, cell and molecular levels, and determine that MZF1 is the most important target for intervention. We aim to rovide new ideas for the treatment of DGP.