DRG中AGEs通过调节Kv4.2参与糖尿病模型大鼠胃高敏感的发生  

AGEs in DRG Participates in Gastric Hypersensitivity by Regulating Expression of Kv4.2 in Diabetes Mellitus Rat Model

作　　者：王佳浩 俞汀[1] 姜柳琴[1] WANG Jiahao;YU Ting;JIANG Liuqin(Department of Gastroenterology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,210029)

机构地区：[1]南京医科大学第一附属医院消化内科,210029

出　　处：《胃肠病学》2022年第5期263-269,共7页Chinese Journal of Gastroenterology

基　　金：国家自然科学基金(82000508)。

摘　　要：背景:糖尿病胃轻瘫(DGP)是最常见的糖尿病(DM)并发症之一,其主要症状包括上腹痛、恶心、呕吐、腹胀等,胃高敏感是DGP的主要发病机制。晚期糖基化终末产物(AGEs)是诱发DM慢性并发症的始动因素,其与胃高敏感的关系尚未明确。Kv4.2通道在调控内脏感觉中起有重要作用,Kv4.2亚单位失活可降低钾电流,增强痛觉感受,提高胃敏感性。目的:探讨AGEs通过影响Kv4.2通道的表达或活性参与DM模型大鼠胃高敏感的机制。方法:54只大鼠随机分为对照组、DM组和DM+AG组,腹腔注射链脲菌素(STZ)诱导DM大鼠模型。监测大鼠血糖、体质量、胃敏感性和胃排空率;蛋白质印迹法、ELISA法分别检测胃组织和血清CML含量;免疫荧光法检测脊髓背根神经节(DRG)中RAGE表达及其与Kv4.2共表达情况;蛋白质印迹法检测DRG神经元RAGE表达和ERK1/2、Kv4.2磷酸化水平。结果:与对照组相比,DM组大鼠胃敏感性显著增加(P<0.01),胃排空率显著降低(P<0.05),AGEs标志物血清和胃组织中CML含量显著升高(P<0.05),DRG神经元中RAGE与Kv4.2共表达率显著升高(P<0.01),ERK1/2、Kv4.2磷酸化水平显著上调(P<0.05)。给予AG干预后,上述指标均明显改善(P<0.05)。结论:AGEs是导致DM模型大鼠胃高敏感的上游因素。AGEs通过抑制Kv4.2通道增加DRG神经元兴奋性,导致胃高敏感。RAGE、ERK1/2信号可能参与上述过程。Diabetic gastroparesis(DGP)is one of the most common complications of diabetes mellitus(DM),and its main symptoms include upper abdominal pain,nausea,vomiting,abdominal distension,etc.Gastric hypersensitivity is the main pathogenesis of DGP.Advanced glycation end products(AGEs)is the initiating factor of chronic complications of DM,and its relationship with gastric hypersensitivity has not yet been clear.Kv4.2 channel plays an important role in regulating visceral sensation.Subunit inactivation of Kv4.2 can reduce potassium current,enhance pain sensation,and increase gastric sensitivity.Aims:To investigate the mechanism of AGEs participating in gastric hypersensitivity by regulating the expression or activity of Kv4.2 channel in DM rat model.Methods:Fifty⁃four rats were randomly divided into control group,DM group and DM+AG group.Streptozocin(STZ)was intraperitoneally injected to induce DM rat model.Blood glucose,body weight,gastric sensitivity and gastric emptying rate were monitored.Western blotting and ELISA were used to detect CML content in stomach tissue and serum,respectively.The expression of RAGE and its co⁃expression with Kv4.2 in dorsal root ganglia(DRG)neurons were detected by immunofluorescence.Western blotting was used to detect RAGE expression and phosphorylation levels of ERK1/2 and Kv4.2 in DRG neurons.Results:Compared with control group,gastric sensitivity was significantly increased in DM group(P<0.01),gastric emptying rate was significantly decreased(P<0.05),AGEs marker CML content in serum and gastric tissue were significantly increased(P<0.05),co⁃expression rate of RAGE and Kv4.2 in DRG neurons was significantly increased(P<0.01),and phosphorylation levels of ERK1/2 and Kv4.2 were up⁃regulated(P<0.05).After intervention with AG,above⁃mentioned indices were significantly ameliorated(P<0.05).Conclusions:AGEs is an upstream factor leading to gastric hypersensitivity in DM rat model.AGEs increases the excitability of DRG neurons by inhibiting Kv4.2 channel,leading to gastric hypersensi

关 键 词：糖尿病 胃肌轻瘫 背根神经节 晚期糖基化终末产物 Kv4.2通道 

分 类 号：R587.1[医药卫生—内分泌] R-332[医药卫生—内科学]